Nutrient chapter

Sildenafil

Sildenafil. A competitive inhibitor of phosphodiesterase type 5 that does not generate a signal but prevents one being cleared: it occupies the catalytic site with an inhibition constant of 1 nanomolar against a cyclic GMP Michaelis constant of 2000 nanomolar, so cyclic GMP made by guanylate cyclase in response to nitric oxide survives longer. Without nitric oxide drive it had no functional effect on isolated cavernosal tissue and did not raise intracavernosal pressure in the anaesthetised dog until the pelvic nerve was stimulated, though whether that requirement is absolute is recorded here as an open disagreement. Because organic nitrates raise the same messenger at a different point on the same pathway, the two potentiate rather than add, and a sublingual nitrate tablet produced a fourfold greater fall in systolic pressure. The target enzyme is present in cavernosal and vascular smooth muscle, platelets and the pulmonary arterial wall and is not detectable in human cardiac ventricle. Selectivity is 80 to 19,000-fold over PDE1 to PDE4 but only about tenfold over retinal PDE6, which is the basis of the visual effects. It is recorded as an entity distinct from its active N-desmethyl metabolite, and its target is recorded as distinct from PDE6, with neither pair linked as a family. Species, exposure and limitations are retained in each linked claim.

40 recorded mechanisms · 4 availability situations · 1 preserved sources. Draft and verified records are labeled separately.

Read recorded mechanisms Open recursive mind map

The mechanisms

What the sources say this nutrient does, one relationship at a time. Plain wording comes first; the technical statement follows.

Both cyclic GMP and cyclic AMP specific phosphodiesterases were identified in human corpora cavernosa in vitro, the main phosphodiesterase activity in this tissue being due to PDE5 with PDE2 and PDE3 also identified, and sildenafil is a selective inhibitor of PDE5 with a mean half-maximal inhibitory concentration of 0.0039 micromolar.
Phosphodiesterase 5 family → Human corpus cavernosum trabecular smooth muscle source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/sildenafil-research/8858389.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "173f69debd8427b8a1c001e543e4356f2d3b90c730ca3217073a25c4bc61905a", "start_char": 0, "end_char": 1288, "text_sha256": "173f69debd8427b8a1c001e543e4356f2d3b90c730ca3217073a25c4bc61905a"}
experimental_model
Phosphodiesterase isozyme characterisation in human corpora cavernosa with volunteer pharmacokinetics and a small clinical study
exposure
Sildenafil assayed against phosphodiesterase isozymes prepared from human tissue
limitations
The first report of the compound. The clinical arm is twelve patients without an established organic cause, so it establishes the target rather than the treatment effect.
nutrient_topic
Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. · Sildenafil
organism
Human
plain_language
One of the several enzymes in this tissue carries most of the activity, and the drug was built against that one.
primary_references
[sil-p8858389] Sildenafil: an orally active type 5 cyclic GMP-specific phosphodiesterase inhibitor for the treatment of penile erectile dysfunction. (1996). https://pubmed.ncbi.nlm.nih.gov/8858389/
tissue_or_cell_type
Corpus cavernosum
Sildenafil: the enzyme it occupies instead of the substrate, why it cannot start a signal it can only preserve, the organic nitrate interaction that follows from that, the homologous retinal enzyme ten-fold away, and the pulmonary circulation where the same mechanism became a second indication (2026-09-22) · lines 119–130
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Phosphodiesterase isozyme characterisation in human corpora cavernosa with volunteer pharmacokinetics and a small clinical study · source_derived_draft · unverified_draft
### sil-pde5-is-the-main-isozyme Both cyclic GMP and cyclic AMP specific phosphodiesterases were identified in human corpora cavernosa in vitro, the main phosphodiesterase activity in this tissue being due to PDE5 with PDE2 and PDE3 also identified, and sildenafil is a selective inhibitor of PDE5 with a mean half-maximal inhibitory concentration of 0.0039 micromolar. Condition category: normal nutrient_topic: Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. plain_language: One of the several enzymes in this tissue carries most of the activity, and the drug was built against that one. organism: Human tissue_or_cell_type: Corpus cavernosum experimental_model: Phosphodiesterase isozyme characterisation in human corpora cavernosa with volunteer pharmacokinetics and a small clinical study limitations: The first report of the compound. The clinical arm is twelve patients without an established organic cause, so it establishes the target rather than the treatment effect. exposure: Sildenafil assayed against phosphodiesterase isozymes prepared from human tissue evidence_span: {"source_cache": "artifacts/sildenafil-research/8858389.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "173f69debd8427b8a1c001e543e4356f2d3b90c730ca3217073a25c4bc61905a", "start_char": 0, "end_char": 1288, "text_sha256": "173f69debd8427b8a1c001e543e4356f2d3b90c730ca3217073a25c4bc61905a"} [sil-p8858389] Sildenafil: an orally active type 5 cyclic GMP-specific phosphodiesterase inhibitor for the treatment of penile erectile dysfunction. (1996). https://pubmed.ncbi.nlm.nih.gov/8858389/
Complete structured claim and evidence
Sildenafil inhibited PDE5 from human corpus cavernosum with a geometric mean half-maximal inhibitory concentration of 3.5 nanomolar and was approximately 240-fold more potent than zaprinast, values for inhibition of PDE1 to PDE4 were 80 to more than 8500 times greater than that for PDE5, and the value for PDE6 at 33 nanomolar was approximately 9-fold greater.
Sildenafil → Phosphodiesterase 5 family source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/sildenafil-research/9598563.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "860e09237bbae4ec5bb65a640186902908ccb9c6ec502b504a1ecddbb33810a2", "start_char": 0, "end_char": 1755, "text_sha256": "860e09237bbae4ec5bb65a640186902908ccb9c6ec502b504a1ecddbb33810a2"}
experimental_model
Isolated human corpus cavernosum strips with electrical field stimulation, and phosphodiesterase assays across families 1 to 6
exposure
Sildenafil against PDE1 to PDE5 prepared from human tissues and PDE6 from bovine retina, with zaprinast as comparator
limitations
Measures the full selectivity series in one laboratory using the same method, which is what makes the ratios comparable. The PDE6 preparation is bovine retina rather than human.
nutrient_topic
Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. · Sildenafil
organism
Human and bovine enzyme
plain_language
It is hundreds to thousands of times more selective against most of the enzyme family, and only about nine times against the one in the retina.
primary_references
[sil-p9598563] Effects of sildenafil on the relaxation of human corpus cavernosum tissue in vitro and on the activities of cyclic nucleotide phosphodiesterase isozymes. (1998). https://pubmed.ncbi.nlm.nih.gov/9598563/ DOI: 10.1016/s0022-5347(01)63299-3
tissue_or_cell_type
Corpus cavernosum and bovine retina
Sildenafil: the enzyme it occupies instead of the substrate, why it cannot start a signal it can only preserve, the organic nitrate interaction that follows from that, the homologous retinal enzyme ten-fold away, and the pulmonary circulation where the same mechanism became a second indication (2026-09-22) · lines 132–143
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Isolated human corpus cavernosum strips with electrical field stimulation, and phosphodiesterase assays across families 1 to 6 · source_derived_draft · unverified_draft
### sil-the-selectivity-series Sildenafil inhibited PDE5 from human corpus cavernosum with a geometric mean half-maximal inhibitory concentration of 3.5 nanomolar and was approximately 240-fold more potent than zaprinast, values for inhibition of PDE1 to PDE4 were 80 to more than 8500 times greater than that for PDE5, and the value for PDE6 at 33 nanomolar was approximately 9-fold greater. Condition category: normal nutrient_topic: Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. plain_language: It is hundreds to thousands of times more selective against most of the enzyme family, and only about nine times against the one in the retina. organism: Human and bovine enzyme tissue_or_cell_type: Corpus cavernosum and bovine retina experimental_model: Isolated human corpus cavernosum strips with electrical field stimulation, and phosphodiesterase assays across families 1 to 6 limitations: Measures the full selectivity series in one laboratory using the same method, which is what makes the ratios comparable. The PDE6 preparation is bovine retina rather than human. exposure: Sildenafil against PDE1 to PDE5 prepared from human tissues and PDE6 from bovine retina, with zaprinast as comparator evidence_span: {"source_cache": "artifacts/sildenafil-research/9598563.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "860e09237bbae4ec5bb65a640186902908ccb9c6ec502b504a1ecddbb33810a2", "start_char": 0, "end_char": 1755, "text_sha256": "860e09237bbae4ec5bb65a640186902908ccb9c6ec502b504a1ecddbb33810a2"} [sil-p9598563] Effects of sildenafil on the relaxation of human corpus cavernosum tissue in vitro and on the activities of cyclic nucleotide phosphodiesterase isozymes. (1998). https://pubmed.ncbi.nlm.nih.gov/9598563/ DOI: 10.1016/s0022-5347(01)63299-3
Complete structured claim and evidence
Sildenafil at 0.001 to 1 micromolar enhanced the electrical-field-stimulation-induced, nitric-oxide-dependent relaxation of human corpus cavernosum in a concentration-dependent manner to a maximum of three times the pretreatment level at 1 micromolar, supporting the proposal that the drug acts by potentiating the nitric-oxide-stimulated cyclic GMP signal mediating relaxation of cavernosal smooth muscle during sexual stimulation.
Sildenafil → Relaxation of vascular and trabecular smooth muscle source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/sildenafil-research/9598563.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "860e09237bbae4ec5bb65a640186902908ccb9c6ec502b504a1ecddbb33810a2", "start_char": 0, "end_char": 1755, "text_sha256": "860e09237bbae4ec5bb65a640186902908ccb9c6ec502b504a1ecddbb33810a2"}
experimental_model
Isolated human corpus cavernosum strips with electrical field stimulation, and phosphodiesterase assays across families 1 to 6
exposure
Sildenafil against PDE1 to PDE5 prepared from human tissues and PDE6 from bovine retina, with zaprinast as comparator
limitations
Measures the full selectivity series in one laboratory using the same method, which is what makes the ratios comparable. The PDE6 preparation is bovine retina rather than human.
nutrient_topic
Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. · Sildenafil
organism
Human and bovine enzyme
plain_language
It triples a relaxation the nerves were already producing; it does not produce one of its own.
primary_references
[sil-p9598563] Effects of sildenafil on the relaxation of human corpus cavernosum tissue in vitro and on the activities of cyclic nucleotide phosphodiesterase isozymes. (1998). https://pubmed.ncbi.nlm.nih.gov/9598563/ DOI: 10.1016/s0022-5347(01)63299-3
tissue_or_cell_type
Corpus cavernosum and bovine retina
Sildenafil: the enzyme it occupies instead of the substrate, why it cannot start a signal it can only preserve, the organic nitrate interaction that follows from that, the homologous retinal enzyme ten-fold away, and the pulmonary circulation where the same mechanism became a second indication (2026-09-22) · lines 145–156
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Isolated human corpus cavernosum strips with electrical field stimulation, and phosphodiesterase assays across families 1 to 6 · source_derived_draft · unverified_draft
### sil-amplifies-nitrergic-relaxation Sildenafil at 0.001 to 1 micromolar enhanced the electrical-field-stimulation-induced, nitric-oxide-dependent relaxation of human corpus cavernosum in a concentration-dependent manner to a maximum of three times the pretreatment level at 1 micromolar, supporting the proposal that the drug acts by potentiating the nitric-oxide-stimulated cyclic GMP signal mediating relaxation of cavernosal smooth muscle during sexual stimulation. Condition category: normal nutrient_topic: Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. plain_language: It triples a relaxation the nerves were already producing; it does not produce one of its own. organism: Human and bovine enzyme tissue_or_cell_type: Corpus cavernosum and bovine retina experimental_model: Isolated human corpus cavernosum strips with electrical field stimulation, and phosphodiesterase assays across families 1 to 6 limitations: Measures the full selectivity series in one laboratory using the same method, which is what makes the ratios comparable. The PDE6 preparation is bovine retina rather than human. exposure: Sildenafil against PDE1 to PDE5 prepared from human tissues and PDE6 from bovine retina, with zaprinast as comparator evidence_span: {"source_cache": "artifacts/sildenafil-research/9598563.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "860e09237bbae4ec5bb65a640186902908ccb9c6ec502b504a1ecddbb33810a2", "start_char": 0, "end_char": 1755, "text_sha256": "860e09237bbae4ec5bb65a640186902908ccb9c6ec502b504a1ecddbb33810a2"} [sil-p9598563] Effects of sildenafil on the relaxation of human corpus cavernosum tissue in vitro and on the activities of cyclic nucleotide phosphodiesterase isozymes. (1998). https://pubmed.ncbi.nlm.nih.gov/9598563/ DOI: 10.1016/s0022-5347(01)63299-3
Complete structured claim and evidence
Sildenafil and zaprinast are both competitive inhibitors of PDE5 and double-inhibition analysis shows they interact with the catalytic site in a mutually exclusive manner, with inhibition constants of 1 nanomolar for sildenafil, 5 nanomolar for UK-122764 and 130 nanomolar for zaprinast, and the affinity of each of these inhibitors for the enzyme is much higher than that of cyclic GMP itself whose Michaelis constant is 2000 nanomolar.
Sildenafil → The catalytic site of phosphodiesterase type 5 source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/sildenafil-research/10385692.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "9ce2e7f3f2d22246734a6f998124d7a57cc0eded673f321bbc47586fd2ea3bcf", "start_char": 0, "end_char": 1888, "text_sha256": "9ce2e7f3f2d22246734a6f998124d7a57cc0eded673f321bbc47586fd2ea3bcf"}
experimental_model
Kinetic and site-directed mutagenesis analysis of inhibitor interaction with the phosphodiesterase type 5 catalytic domain
exposure
Sildenafil, UK-122764 and zaprinast against wild-type enzyme and 23 conserved catalytic-domain point mutants
limitations
Places the drug at the catalytic site by competition and by a mutant series, and gives the comparison with the natural substrate that makes the affinity meaningful. Recombinant enzyme.
nutrient_topic
Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. · Sildenafil
organism
Enzyme
plain_language
The drug holds the working part of the enzyme about two thousand times more tightly than the molecule the enzyme is meant to destroy.
primary_references
[sil-p10385692] Inhibition of cyclic GMP-binding cyclic GMP-specific phosphodiesterase (Type 5) by sildenafil and related compounds. (1999). https://pubmed.ncbi.nlm.nih.gov/10385692/ DOI: 10.1124/mol.56.1.124
tissue_or_cell_type
Recombinant phosphodiesterase type 5
Sildenafil: the enzyme it occupies instead of the substrate, why it cannot start a signal it can only preserve, the organic nitrate interaction that follows from that, the homologous retinal enzyme ten-fold away, and the pulmonary circulation where the same mechanism became a second indication (2026-09-22) · lines 158–169
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Kinetic and site-directed mutagenesis analysis of inhibitor interaction with the phosphodiesterase type 5 catalytic domain · source_derived_draft · unverified_draft
### sil-two-thousand-fold-over-substrate Sildenafil and zaprinast are both competitive inhibitors of PDE5 and double-inhibition analysis shows they interact with the catalytic site in a mutually exclusive manner, with inhibition constants of 1 nanomolar for sildenafil, 5 nanomolar for UK-122764 and 130 nanomolar for zaprinast, and the affinity of each of these inhibitors for the enzyme is much higher than that of cyclic GMP itself whose Michaelis constant is 2000 nanomolar. Condition category: normal nutrient_topic: Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. plain_language: The drug holds the working part of the enzyme about two thousand times more tightly than the molecule the enzyme is meant to destroy. organism: Enzyme tissue_or_cell_type: Recombinant phosphodiesterase type 5 experimental_model: Kinetic and site-directed mutagenesis analysis of inhibitor interaction with the phosphodiesterase type 5 catalytic domain limitations: Places the drug at the catalytic site by competition and by a mutant series, and gives the comparison with the natural substrate that makes the affinity meaningful. Recombinant enzyme. exposure: Sildenafil, UK-122764 and zaprinast against wild-type enzyme and 23 conserved catalytic-domain point mutants evidence_span: {"source_cache": "artifacts/sildenafil-research/10385692.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "9ce2e7f3f2d22246734a6f998124d7a57cc0eded673f321bbc47586fd2ea3bcf", "start_char": 0, "end_char": 1888, "text_sha256": "9ce2e7f3f2d22246734a6f998124d7a57cc0eded673f321bbc47586fd2ea3bcf"} [sil-p10385692] Inhibition of cyclic GMP-binding cyclic GMP-specific phosphodiesterase (Type 5) by sildenafil and related compounds. (1999). https://pubmed.ncbi.nlm.nih.gov/10385692/ DOI: 10.1124/mol.56.1.124
Complete structured claim and evidence
After site-directed mutagenesis of each of 23 conserved amino acid residues in the catalytic domain, the pattern of changes in inhibitory concentration for sildenafil was most similar to that found for the affinity of cyclic GMP itself, implying similar interactions with the catalytic domain, and residues such as Tyr602, His607, His643 and Asp754 may form important interactions for sildenafil, but because these amino acids are conserved in all mammalian phosphodiesterases the selectivity and potency of the drug is likely to be provided by a nonconserved residue or residues; sildenafil also stimulates cyclic GMP binding to the allosteric sites by interacting at the catalytic site without competing for the allosteric sites themselves.
Catalytic domain residues Tyr602, His607, His643 and Asp754 of phosphodiesterase type 5 → Sildenafil source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/sildenafil-research/10385692.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "9ce2e7f3f2d22246734a6f998124d7a57cc0eded673f321bbc47586fd2ea3bcf", "start_char": 0, "end_char": 1888, "text_sha256": "9ce2e7f3f2d22246734a6f998124d7a57cc0eded673f321bbc47586fd2ea3bcf"}
experimental_model
Kinetic and site-directed mutagenesis analysis of inhibitor interaction with the phosphodiesterase type 5 catalytic domain
exposure
Sildenafil, UK-122764 and zaprinast against wild-type enzyme and 23 conserved catalytic-domain point mutants
limitations
Places the drug at the catalytic site by competition and by a mutant series, and gives the comparison with the natural substrate that makes the affinity meaningful. Recombinant enzyme.
nutrient_topic
Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. · Sildenafil
organism
Enzyme
plain_language
The residues it grips are the same ones every enzyme in the family has, so what makes it selective is something else.
primary_references
[sil-p10385692] Inhibition of cyclic GMP-binding cyclic GMP-specific phosphodiesterase (Type 5) by sildenafil and related compounds. (1999). https://pubmed.ncbi.nlm.nih.gov/10385692/ DOI: 10.1124/mol.56.1.124
tissue_or_cell_type
Recombinant phosphodiesterase type 5
Sildenafil: the enzyme it occupies instead of the substrate, why it cannot start a signal it can only preserve, the organic nitrate interaction that follows from that, the homologous retinal enzyme ten-fold away, and the pulmonary circulation where the same mechanism became a second indication (2026-09-22) · lines 171–182
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Kinetic and site-directed mutagenesis analysis of inhibitor interaction with the phosphodiesterase type 5 catalytic domain · source_derived_draft · unverified_draft
### sil-selectivity-is-not-in-the-conserved-residues After site-directed mutagenesis of each of 23 conserved amino acid residues in the catalytic domain, the pattern of changes in inhibitory concentration for sildenafil was most similar to that found for the affinity of cyclic GMP itself, implying similar interactions with the catalytic domain, and residues such as Tyr602, His607, His643 and Asp754 may form important interactions for sildenafil, but because these amino acids are conserved in all mammalian phosphodiesterases the selectivity and potency of the drug is likely to be provided by a nonconserved residue or residues; sildenafil also stimulates cyclic GMP binding to the allosteric sites by interacting at the catalytic site without competing for the allosteric sites themselves. Condition category: normal nutrient_topic: Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. plain_language: The residues it grips are the same ones every enzyme in the family has, so what makes it selective is something else. organism: Enzyme tissue_or_cell_type: Recombinant phosphodiesterase type 5 experimental_model: Kinetic and site-directed mutagenesis analysis of inhibitor interaction with the phosphodiesterase type 5 catalytic domain limitations: Places the drug at the catalytic site by competition and by a mutant series, and gives the comparison with the natural substrate that makes the affinity meaningful. Recombinant enzyme. exposure: Sildenafil, UK-122764 and zaprinast against wild-type enzyme and 23 conserved catalytic-domain point mutants evidence_span: {"source_cache": "artifacts/sildenafil-research/10385692.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "9ce2e7f3f2d22246734a6f998124d7a57cc0eded673f321bbc47586fd2ea3bcf", "start_char": 0, "end_char": 1888, "text_sha256": "9ce2e7f3f2d22246734a6f998124d7a57cc0eded673f321bbc47586fd2ea3bcf"} [sil-p10385692] Inhibition of cyclic GMP-binding cyclic GMP-specific phosphodiesterase (Type 5) by sildenafil and related compounds. (1999). https://pubmed.ncbi.nlm.nih.gov/10385692/ DOI: 10.1124/mol.56.1.124
Complete structured claim and evidence
Mutations affecting cyclic GMP binding to either one or both allosteric sites of phosphodiesterase type 5 do not influence cyclic GMP hydrolysis at the catalytic site under the conditions used, but the mutants defective in binding at either site require much higher cyclic GMP concentrations for allosteric stimulation of phosphorylation, while a mutant with higher binding affinity is phosphorylated at lower cyclic GMP concentrations, so binding to the allosteric sites does not directly affect catalysis but regulates phosphorylation of the enzyme.
The two tandem allosteric cyclic GMP binding sites of phosphodiesterase type 5 → Phosphodiesterase type 5 phosphorylated at serine 92 source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/sildenafil-research/9445376.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "f59d258bd35b229b3455ab2d15e1d21fbe5a475a1b936ecd423eb49c9a9aea29", "start_char": 0, "end_char": 1541, "text_sha256": "f59d258bd35b229b3455ab2d15e1d21fbe5a475a1b936ecd423eb49c9a9aea29"}
experimental_model
Site-directed mutagenesis of the two tandem allosteric cyclic GMP binding sites of phosphodiesterase type 5
exposure
D289A, D478A and D289A/D478A binding-site mutants, with phosphorylation by the catalytic subunit of cyclic AMP-dependent protein kinase
limitations
Separates what the allosteric sites do from what the catalytic site does, using mutants that lose binding at one site, the other, or both.
nutrient_topic
Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. · Sildenafil
organism
Enzyme
plain_language
The second pair of binding sites does not change how fast the enzyme works; it decides when the enzyme gets switched up.
primary_references
[sil-p9445376] Binding of cGMP to both allosteric sites of cGMP-binding cGMP-specific phosphodiesterase (PDE5) is required for its phosphorylation. (1998). https://pubmed.ncbi.nlm.nih.gov/9445376/ DOI: 10.1042/bj3290505
tissue_or_cell_type
Recombinant phosphodiesterase type 5
Sildenafil: the enzyme it occupies instead of the substrate, why it cannot start a signal it can only preserve, the organic nitrate interaction that follows from that, the homologous retinal enzyme ten-fold away, and the pulmonary circulation where the same mechanism became a second indication (2026-09-22) · lines 184–195
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Site-directed mutagenesis of the two tandem allosteric cyclic GMP binding sites of phosphodiesterase type 5 · source_derived_draft · unverified_draft
### sil-allosteric-sites-gate-phosphorylation Mutations affecting cyclic GMP binding to either one or both allosteric sites of phosphodiesterase type 5 do not influence cyclic GMP hydrolysis at the catalytic site under the conditions used, but the mutants defective in binding at either site require much higher cyclic GMP concentrations for allosteric stimulation of phosphorylation, while a mutant with higher binding affinity is phosphorylated at lower cyclic GMP concentrations, so binding to the allosteric sites does not directly affect catalysis but regulates phosphorylation of the enzyme. Condition category: normal nutrient_topic: Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. plain_language: The second pair of binding sites does not change how fast the enzyme works; it decides when the enzyme gets switched up. organism: Enzyme tissue_or_cell_type: Recombinant phosphodiesterase type 5 experimental_model: Site-directed mutagenesis of the two tandem allosteric cyclic GMP binding sites of phosphodiesterase type 5 limitations: Separates what the allosteric sites do from what the catalytic site does, using mutants that lose binding at one site, the other, or both. exposure: D289A, D478A and D289A/D478A binding-site mutants, with phosphorylation by the catalytic subunit of cyclic AMP-dependent protein kinase evidence_span: {"source_cache": "artifacts/sildenafil-research/9445376.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "f59d258bd35b229b3455ab2d15e1d21fbe5a475a1b936ecd423eb49c9a9aea29", "start_char": 0, "end_char": 1541, "text_sha256": "f59d258bd35b229b3455ab2d15e1d21fbe5a475a1b936ecd423eb49c9a9aea29"} [sil-p9445376] Binding of cGMP to both allosteric sites of cGMP-binding cGMP-specific phosphodiesterase (PDE5) is required for its phosphorylation. (1998). https://pubmed.ncbi.nlm.nih.gov/9445376/ DOI: 10.1042/bj3290505
Complete structured claim and evidence
Prior incubation of recombinant phosphodiesterase type 5 with protein kinase G, magnesium ATP and cyclic GMP, producing serine 92 phosphorylation, caused a 50 to 70% increase in enzyme activity and increased the affinity of cyclic GMP binding to the allosteric sites, reducing the concentration needed for half-maximum allosteric binding from 0.13 to 0.03 micromolar, with stimulation obtained at 0.2 to 0.5 micromolar kinase subunit which is approximately the cellular level in vascular smooth muscle, while considerably higher concentrations of protein kinase A were required.
cGMP-dependent protein kinase I → Phosphodiesterase 5 family source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/sildenafil-research/10785399.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "d4048089a01ed860c8a71d096eb5bf1407e19557ca97c88b6cbac0e5f69de171", "start_char": 0, "end_char": 2100, "text_sha256": "d4048089a01ed860c8a71d096eb5bf1407e19557ca97c88b6cbac0e5f69de171"}
experimental_model
Phosphorylation of recombinant bovine phosphodiesterase type 5 at serine 92 with activity and binding measurement
exposure
Protein kinase G or the catalytic subunit of protein kinase A with magnesium ATP and cyclic GMP
limitations
Establishes the feedback loop and shows the kinase concentrations are physiological. It also records that phosphorylation does not change the potency of the drug, which matters for whether the loop blunts the drug.
nutrient_topic
Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. · Sildenafil
organism
Cattle enzyme
plain_language
The messenger switches on a kinase that speeds up the enzyme destroying it, which is a brake the cell applies to itself.
primary_references
[sil-p10785399] Phosphorylation of phosphodiesterase-5 by cyclic nucleotide-dependent protein kinase alters its catalytic and allosteric cGMP-binding activities. (2000). https://pubmed.ncbi.nlm.nih.gov/10785399/ DOI: 10.1046/j.1432-1327.2000.01297.x
tissue_or_cell_type
Recombinant enzyme and lung extract
Sildenafil: the enzyme it occupies instead of the substrate, why it cannot start a signal it can only preserve, the organic nitrate interaction that follows from that, the homologous retinal enzyme ten-fold away, and the pulmonary circulation where the same mechanism became a second indication (2026-09-22) · lines 197–208
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Phosphorylation of recombinant bovine phosphodiesterase type 5 at serine 92 with activity and binding measurement · source_derived_draft · unverified_draft
### sil-pkg-feedback-speeds-the-enzyme Prior incubation of recombinant phosphodiesterase type 5 with protein kinase G, magnesium ATP and cyclic GMP, producing serine 92 phosphorylation, caused a 50 to 70% increase in enzyme activity and increased the affinity of cyclic GMP binding to the allosteric sites, reducing the concentration needed for half-maximum allosteric binding from 0.13 to 0.03 micromolar, with stimulation obtained at 0.2 to 0.5 micromolar kinase subunit which is approximately the cellular level in vascular smooth muscle, while considerably higher concentrations of protein kinase A were required. Condition category: normal nutrient_topic: Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. plain_language: The messenger switches on a kinase that speeds up the enzyme destroying it, which is a brake the cell applies to itself. organism: Cattle enzyme tissue_or_cell_type: Recombinant enzyme and lung extract experimental_model: Phosphorylation of recombinant bovine phosphodiesterase type 5 at serine 92 with activity and binding measurement limitations: Establishes the feedback loop and shows the kinase concentrations are physiological. It also records that phosphorylation does not change the potency of the drug, which matters for whether the loop blunts the drug. exposure: Protein kinase G or the catalytic subunit of protein kinase A with magnesium ATP and cyclic GMP evidence_span: {"source_cache": "artifacts/sildenafil-research/10785399.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "d4048089a01ed860c8a71d096eb5bf1407e19557ca97c88b6cbac0e5f69de171", "start_char": 0, "end_char": 2100, "text_sha256": "d4048089a01ed860c8a71d096eb5bf1407e19557ca97c88b6cbac0e5f69de171"} [sil-p10785399] Phosphorylation of phosphodiesterase-5 by cyclic nucleotide-dependent protein kinase alters its catalytic and allosteric cGMP-binding activities. (2000). https://pubmed.ncbi.nlm.nih.gov/10785399/ DOI: 10.1046/j.1432-1327.2000.01297.x
Complete structured claim and evidence
There was no detectable difference between phosphorylated and unphosphorylated phosphodiesterase type 5 in the median inhibitory concentration for sildenafil, or for zaprinast or 3-isobutyl-1-methylxanthine.
Phosphodiesterase type 5 phosphorylated at serine 92 → Sildenafil source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/sildenafil-research/10785399.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "d4048089a01ed860c8a71d096eb5bf1407e19557ca97c88b6cbac0e5f69de171", "start_char": 0, "end_char": 2100, "text_sha256": "d4048089a01ed860c8a71d096eb5bf1407e19557ca97c88b6cbac0e5f69de171"}
experimental_model
Phosphorylation of recombinant bovine phosphodiesterase type 5 at serine 92 with activity and binding measurement
exposure
Protein kinase G or the catalytic subunit of protein kinase A with magnesium ATP and cyclic GMP
limitations
Establishes the feedback loop and shows the kinase concentrations are physiological. It also records that phosphorylation does not change the potency of the drug, which matters for whether the loop blunts the drug.
nutrient_topic
Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. · Sildenafil
organism
Cattle enzyme
plain_language
Speeding the enzyme up does not make it any harder for the drug to block.
primary_references
[sil-p10785399] Phosphorylation of phosphodiesterase-5 by cyclic nucleotide-dependent protein kinase alters its catalytic and allosteric cGMP-binding activities. (2000). https://pubmed.ncbi.nlm.nih.gov/10785399/ DOI: 10.1046/j.1432-1327.2000.01297.x
tissue_or_cell_type
Recombinant enzyme and lung extract
Sildenafil: the enzyme it occupies instead of the substrate, why it cannot start a signal it can only preserve, the organic nitrate interaction that follows from that, the homologous retinal enzyme ten-fold away, and the pulmonary circulation where the same mechanism became a second indication (2026-09-22) · lines 210–221
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Phosphorylation of recombinant bovine phosphodiesterase type 5 at serine 92 with activity and binding measurement · source_derived_draft · unverified_draft
### sil-feedback-does-not-blunt-the-drug There was no detectable difference between phosphorylated and unphosphorylated phosphodiesterase type 5 in the median inhibitory concentration for sildenafil, or for zaprinast or 3-isobutyl-1-methylxanthine. Condition category: normal nutrient_topic: Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. plain_language: Speeding the enzyme up does not make it any harder for the drug to block. organism: Cattle enzyme tissue_or_cell_type: Recombinant enzyme and lung extract experimental_model: Phosphorylation of recombinant bovine phosphodiesterase type 5 at serine 92 with activity and binding measurement limitations: Establishes the feedback loop and shows the kinase concentrations are physiological. It also records that phosphorylation does not change the potency of the drug, which matters for whether the loop blunts the drug. exposure: Protein kinase G or the catalytic subunit of protein kinase A with magnesium ATP and cyclic GMP evidence_span: {"source_cache": "artifacts/sildenafil-research/10785399.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "d4048089a01ed860c8a71d096eb5bf1407e19557ca97c88b6cbac0e5f69de171", "start_char": 0, "end_char": 2100, "text_sha256": "d4048089a01ed860c8a71d096eb5bf1407e19557ca97c88b6cbac0e5f69de171"} [sil-p10785399] Phosphorylation of phosphodiesterase-5 by cyclic nucleotide-dependent protein kinase alters its catalytic and allosteric cGMP-binding activities. (2000). https://pubmed.ncbi.nlm.nih.gov/10785399/ DOI: 10.1046/j.1432-1327.2000.01297.x
Complete structured claim and evidence
The isolated first GAF domain of phosphodiesterase type 5 binds cyclic GMP with a dissociation constant of 650 nanomolar, the binding site identified by homology modelling and site-directed mutagenesis consisting of conserved arginine, asparagine, lysine and aspartate residues, and the structural and binding studies together show that cyclic GMP binding GAF domains form a new class of cyclic nucleotide receptors distinct from the regulatory domains of cyclic nucleotide-regulated protein kinases and ion channels.
The GAF domain of phosphodiesterase type 5 → Cyclic guanosine monophosphate source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/sildenafil-research/11032796.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "c3fde3e8ef99d45fbe9c59a9f4eba5a696b7e212dd2fc6d23999ce724d2996d9", "start_char": 0, "end_char": 1012, "text_sha256": "c3fde3e8ef99d45fbe9c59a9f4eba5a696b7e212dd2fc6d23999ce724d2996d9"}
experimental_model
Crystal structure of a GAF domain at 1.9 angstrom with homology modelling and mutagenesis of the phosphodiesterase type 5 domain
exposure
Cyclic GMP binding to the isolated first GAF domain of phosphodiesterase type 5
limitations
A structure of a related domain plus modelling rather than a structure of the phosphodiesterase domain itself. The binding constant is measured directly.
nutrient_topic
Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. · Sildenafil
organism
Yeast and human protein
plain_language
The regulatory half of the enzyme is itself a receptor for the messenger it destroys.
primary_references
[sil-p11032796] Structure of the GAF domain, a ubiquitous signaling motif and a new class of cyclic GMP receptor. (2000). https://pubmed.ncbi.nlm.nih.gov/11032796/ DOI: 10.1093/emboj/19.20.5288
tissue_or_cell_type
GAF domain
Sildenafil: the enzyme it occupies instead of the substrate, why it cannot start a signal it can only preserve, the organic nitrate interaction that follows from that, the homologous retinal enzyme ten-fold away, and the pulmonary circulation where the same mechanism became a second indication (2026-09-22) · lines 223–234
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Crystal structure of a GAF domain at 1.9 angstrom with homology modelling and mutagenesis of the phosphodiesterase type 5 domain · source_derived_draft · unverified_draft
### sil-gaf-is-a-nucleotide-receptor The isolated first GAF domain of phosphodiesterase type 5 binds cyclic GMP with a dissociation constant of 650 nanomolar, the binding site identified by homology modelling and site-directed mutagenesis consisting of conserved arginine, asparagine, lysine and aspartate residues, and the structural and binding studies together show that cyclic GMP binding GAF domains form a new class of cyclic nucleotide receptors distinct from the regulatory domains of cyclic nucleotide-regulated protein kinases and ion channels. Condition category: normal nutrient_topic: Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. plain_language: The regulatory half of the enzyme is itself a receptor for the messenger it destroys. organism: Yeast and human protein tissue_or_cell_type: GAF domain experimental_model: Crystal structure of a GAF domain at 1.9 angstrom with homology modelling and mutagenesis of the phosphodiesterase type 5 domain limitations: A structure of a related domain plus modelling rather than a structure of the phosphodiesterase domain itself. The binding constant is measured directly. exposure: Cyclic GMP binding to the isolated first GAF domain of phosphodiesterase type 5 evidence_span: {"source_cache": "artifacts/sildenafil-research/11032796.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "c3fde3e8ef99d45fbe9c59a9f4eba5a696b7e212dd2fc6d23999ce724d2996d9", "start_char": 0, "end_char": 1012, "text_sha256": "c3fde3e8ef99d45fbe9c59a9f4eba5a696b7e212dd2fc6d23999ce724d2996d9"} [sil-p11032796] Structure of the GAF domain, a ubiquitous signaling motif and a new class of cyclic GMP receptor. (2000). https://pubmed.ncbi.nlm.nih.gov/11032796/ DOI: 10.1093/emboj/19.20.5288
Complete structured claim and evidence
The newly cloned phosphodiesterase PDE9A1 is highly specific for cyclic GMP with a Michaelis constant of approximately 0.07 micromolar, the lowest yet reported for a phosphodiesterase and at least 40 to 170 times lower than that of PDE5 and PDE6 respectively, it shows highest messenger RNA expression in kidney with lower levels in liver, lung and brain, and when expressed in COS-7 cells its activity was not inhibited well by either the nonselective inhibitor 3-isobutyl-1-methylxanthine or the new selective PDE5 inhibitor sildenafil, while the PDE1 and PDE5 inhibitor SCH51866 inhibited it with a half-maximal concentration of 1.55 micromolar.
Sildenafil → Phosphodiesterase 9A source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/sildenafil-research/9624145.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "ea6afcfbb102bf5a407894b06969c9fe245261fa8a1fea8fb92b201d8b24ace2", "start_char": 0, "end_char": 1265, "text_sha256": "ea6afcfbb102bf5a407894b06969c9fe245261fa8a1fea8fb92b201d8b24ace2"}
experimental_model
Cloning, expression and kinetic characterisation of a newly identified cyclic nucleotide phosphodiesterase family
exposure
Recombinant PDE9A1 against 3-isobutyl-1-methylxanthine, sildenafil and SCH51866
limitations
A cloning and characterisation report. The expression survey is messenger RNA rather than protein, and the enzyme is heterologously expressed.
nutrient_topic
Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. · Sildenafil
organism
Mouse
plain_language
There is another enzyme that destroys the same messenger even more avidly, and this drug does not touch it.
primary_references
[sil-p9624145] Identification and characterization of a novel family of cyclic nucleotide phosphodiesterases. (1998). https://pubmed.ncbi.nlm.nih.gov/9624145/ DOI: 10.1074/jbc.273.25.15553
tissue_or_cell_type
Kidney, liver, lung and brain messenger RNA
Sildenafil: the enzyme it occupies instead of the substrate, why it cannot start a signal it can only preserve, the organic nitrate interaction that follows from that, the homologous retinal enzyme ten-fold away, and the pulmonary circulation where the same mechanism became a second indication (2026-09-22) · lines 236–247
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Cloning, expression and kinetic characterisation of a newly identified cyclic nucleotide phosphodiesterase family · source_derived_draft · unverified_draft
### sil-another-cgmp-enzyme-it-misses The newly cloned phosphodiesterase PDE9A1 is highly specific for cyclic GMP with a Michaelis constant of approximately 0.07 micromolar, the lowest yet reported for a phosphodiesterase and at least 40 to 170 times lower than that of PDE5 and PDE6 respectively, it shows highest messenger RNA expression in kidney with lower levels in liver, lung and brain, and when expressed in COS-7 cells its activity was not inhibited well by either the nonselective inhibitor 3-isobutyl-1-methylxanthine or the new selective PDE5 inhibitor sildenafil, while the PDE1 and PDE5 inhibitor SCH51866 inhibited it with a half-maximal concentration of 1.55 micromolar. Condition category: normal nutrient_topic: Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. plain_language: There is another enzyme that destroys the same messenger even more avidly, and this drug does not touch it. organism: Mouse tissue_or_cell_type: Kidney, liver, lung and brain messenger RNA experimental_model: Cloning, expression and kinetic characterisation of a newly identified cyclic nucleotide phosphodiesterase family limitations: A cloning and characterisation report. The expression survey is messenger RNA rather than protein, and the enzyme is heterologously expressed. exposure: Recombinant PDE9A1 against 3-isobutyl-1-methylxanthine, sildenafil and SCH51866 evidence_span: {"source_cache": "artifacts/sildenafil-research/9624145.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "ea6afcfbb102bf5a407894b06969c9fe245261fa8a1fea8fb92b201d8b24ace2", "start_char": 0, "end_char": 1265, "text_sha256": "ea6afcfbb102bf5a407894b06969c9fe245261fa8a1fea8fb92b201d8b24ace2"} [sil-p9624145] Identification and characterization of a novel family of cyclic nucleotide phosphodiesterases. (1998). https://pubmed.ncbi.nlm.nih.gov/9624145/ DOI: 10.1074/jbc.273.25.15553
Complete structured claim and evidence
Image analysis of purified bovine rod phosphodiesterase 6 revealed the three-dimensional dimeric arrangement of the alpha-beta-delta complex and the internal organization of each catalytic subunit into three distinct domains corresponding to the catalytic and two GAF domains, and the three-dimensional molecular organization of human platelet phosphodiesterase type 5 appears highly homologous to that of bovine rod phosphodiesterase 6 as predicted by similarities in their primary sequences.
Rod PDE6 complex → Phosphodiesterase 5 family source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/sildenafil-research/11453687.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "54fdc1cf336b81568055fa21b19ad21600db5bf276dc5dc9e1dcb490cb63de30", "start_char": 0, "end_char": 1312, "text_sha256": "54fdc1cf336b81568055fa21b19ad21600db5bf276dc5dc9e1dcb490cb63de30"}
experimental_model
Electron microscopy and single-particle image analysis of purified bovine rod phosphodiesterase 6
exposure
Solubilised rod PDE6 depleted of its gamma subunits, with immunolabelling
limitations
A structural comparison at 2.8 nanometre resolution rather than atomic detail. The comparison with PDE5 is inferred from sequence similarity and the reconstructed organisation.
nutrient_topic
Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. · Sildenafil
organism
Cattle
plain_language
The retinal enzyme and the target enzyme are built to the same plan, which is why a drug for one reaches the other.
primary_references
[sil-p11453687] Molecular organization of bovine rod cGMP-phosphodiesterase 6. (2001). https://pubmed.ncbi.nlm.nih.gov/11453687/ DOI: 10.1006/jmbi.2001.4813
tissue_or_cell_type
Retinal rod outer segment
Sildenafil: the enzyme it occupies instead of the substrate, why it cannot start a signal it can only preserve, the organic nitrate interaction that follows from that, the homologous retinal enzyme ten-fold away, and the pulmonary circulation where the same mechanism became a second indication (2026-09-22) · lines 249–260
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Electron microscopy and single-particle image analysis of purified bovine rod phosphodiesterase 6 · source_derived_draft · unverified_draft
### sil-pde5-and-pde6-are-built-alike Image analysis of purified bovine rod phosphodiesterase 6 revealed the three-dimensional dimeric arrangement of the alpha-beta-delta complex and the internal organization of each catalytic subunit into three distinct domains corresponding to the catalytic and two GAF domains, and the three-dimensional molecular organization of human platelet phosphodiesterase type 5 appears highly homologous to that of bovine rod phosphodiesterase 6 as predicted by similarities in their primary sequences. Condition category: normal nutrient_topic: Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. plain_language: The retinal enzyme and the target enzyme are built to the same plan, which is why a drug for one reaches the other. organism: Cattle tissue_or_cell_type: Retinal rod outer segment experimental_model: Electron microscopy and single-particle image analysis of purified bovine rod phosphodiesterase 6 limitations: A structural comparison at 2.8 nanometre resolution rather than atomic detail. The comparison with PDE5 is inferred from sequence similarity and the reconstructed organisation. exposure: Solubilised rod PDE6 depleted of its gamma subunits, with immunolabelling evidence_span: {"source_cache": "artifacts/sildenafil-research/11453687.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "54fdc1cf336b81568055fa21b19ad21600db5bf276dc5dc9e1dcb490cb63de30", "start_char": 0, "end_char": 1312, "text_sha256": "54fdc1cf336b81568055fa21b19ad21600db5bf276dc5dc9e1dcb490cb63de30"} [sil-p11453687] Molecular organization of bovine rod cGMP-phosphodiesterase 6. (2001). https://pubmed.ncbi.nlm.nih.gov/11453687/ DOI: 10.1006/jmbi.2001.4813
Complete structured claim and evidence
Sildenafil is a potent competitive inhibitor of PDE5 with a half-maximal inhibitory concentration of 3.5 nanomolar, selective over PDE1 to PDE4 by 80 to 19,000-fold and over retinal PDE6 by 10-fold, it enhanced cyclic GMP accumulation driven with sodium nitroprusside in rabbit corpus cavernosum without affecting cyclic AMP, and in the absence of nitric oxide drive it had no functional effect on human and rabbit isolated corpus cavernosum but potently potentiated the relaxant effects of nitric oxide on these tissues.
Sildenafil → Relaxation of vascular and trabecular smooth muscle source_derived_draftungraded
Experimental context and source evidence
availability_state
biomarker_context Imported condition classification; unverified.
evidence_span
{"source_cache": "artifacts/sildenafil-research/10629850.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "af056c516b44e35eac7b0511ba3a8403ed84c347af6094ebc153f68c8ee7db92", "start_char": 0, "end_char": 2057, "text_sha256": "af056c516b44e35eac7b0511ba3a8403ed84c347af6094ebc153f68c8ee7db92"}
experimental_model
Enzyme selectivity panel with isolated tissue, anaesthetised dog haemodynamics and isolated retina
exposure
Sildenafil with and without nitric oxide drive, and against glyceryl trinitrate, sodium nitroprusside and milrinone
limitations
The single most complete pharmacological characterisation here, covering the target, the absence of effect without upstream drive, the nitrate potentiation, the absence of an inotropic effect, and the retinal effect in one series.
nutrient_topic
Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. · Sildenafil
organism
Human, rabbit and dog
plain_language
With no signal present the drug does nothing; its entire action is to keep an existing signal from being cleared.
primary_references
[sil-p10629850] The pharmacology of sildenafil, a novel and selective inhibitor of phosphodiesterase (PDE) type 5. (1999). https://pubmed.ncbi.nlm.nih.gov/10629850/ DOI: 10.1254/fpj.114.supplement_22
tissue_or_cell_type
Corpus cavernosum, aorta, cardiac trabeculae and retina
trigger_kind
biomarker_context Imported condition classification; unverified.
Sildenafil: the enzyme it occupies instead of the substrate, why it cannot start a signal it can only preserve, the organic nitrate interaction that follows from that, the homologous retinal enzyme ten-fold away, and the pulmonary circulation where the same mechanism became a second indication (2026-09-22) · lines 262–273
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Enzyme selectivity panel with isolated tissue, anaesthetised dog haemodynamics and isolated retina · source_derived_draft · unverified_draft
### sil-no-effect-without-nitric-oxide Sildenafil is a potent competitive inhibitor of PDE5 with a half-maximal inhibitory concentration of 3.5 nanomolar, selective over PDE1 to PDE4 by 80 to 19,000-fold and over retinal PDE6 by 10-fold, it enhanced cyclic GMP accumulation driven with sodium nitroprusside in rabbit corpus cavernosum without affecting cyclic AMP, and in the absence of nitric oxide drive it had no functional effect on human and rabbit isolated corpus cavernosum but potently potentiated the relaxant effects of nitric oxide on these tissues. Condition category: biomarker_context nutrient_topic: Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. plain_language: With no signal present the drug does nothing; its entire action is to keep an existing signal from being cleared. organism: Human, rabbit and dog tissue_or_cell_type: Corpus cavernosum, aorta, cardiac trabeculae and retina experimental_model: Enzyme selectivity panel with isolated tissue, anaesthetised dog haemodynamics and isolated retina limitations: The single most complete pharmacological characterisation here, covering the target, the absence of effect without upstream drive, the nitrate potentiation, the absence of an inotropic effect, and the retinal effect in one series. exposure: Sildenafil with and without nitric oxide drive, and against glyceryl trinitrate, sodium nitroprusside and milrinone evidence_span: {"source_cache": "artifacts/sildenafil-research/10629850.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "af056c516b44e35eac7b0511ba3a8403ed84c347af6094ebc153f68c8ee7db92", "start_char": 0, "end_char": 2057, "text_sha256": "af056c516b44e35eac7b0511ba3a8403ed84c347af6094ebc153f68c8ee7db92"} [sil-p10629850] The pharmacology of sildenafil, a novel and selective inhibitor of phosphodiesterase (PDE) type 5. (1999). https://pubmed.ncbi.nlm.nih.gov/10629850/ DOI: 10.1254/fpj.114.supplement_22
Complete structured claim and evidence
Unlike milrinone, sildenafil had no inotropic effects on dog isolated trabeculae carneae so it is unlikely to have the deleterious effects on cardiac function associated with PDE3 inhibitors, while consistent with its mode of action it potentiated the vasorelaxant effects of glyceryl trinitrate on rabbit isolated aortic rings.
Sildenafil → Myocardial inotropic response source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/sildenafil-research/10629850.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "af056c516b44e35eac7b0511ba3a8403ed84c347af6094ebc153f68c8ee7db92", "start_char": 0, "end_char": 2057, "text_sha256": "af056c516b44e35eac7b0511ba3a8403ed84c347af6094ebc153f68c8ee7db92"}
experimental_model
Enzyme selectivity panel with isolated tissue, anaesthetised dog haemodynamics and isolated retina
exposure
Sildenafil with and without nitric oxide drive, and against glyceryl trinitrate, sodium nitroprusside and milrinone
limitations
The single most complete pharmacological characterisation here, covering the target, the absence of effect without upstream drive, the nitrate potentiation, the absence of an inotropic effect, and the retinal effect in one series.
nutrient_topic
Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. · Sildenafil
organism
Human, rabbit and dog
plain_language
It leaves the heart muscle alone, unlike the drugs that block a different member of the same enzyme family.
primary_references
[sil-p10629850] The pharmacology of sildenafil, a novel and selective inhibitor of phosphodiesterase (PDE) type 5. (1999). https://pubmed.ncbi.nlm.nih.gov/10629850/ DOI: 10.1254/fpj.114.supplement_22
tissue_or_cell_type
Corpus cavernosum, aorta, cardiac trabeculae and retina
Sildenafil: the enzyme it occupies instead of the substrate, why it cannot start a signal it can only preserve, the organic nitrate interaction that follows from that, the homologous retinal enzyme ten-fold away, and the pulmonary circulation where the same mechanism became a second indication (2026-09-22) · lines 275–286
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Enzyme selectivity panel with isolated tissue, anaesthetised dog haemodynamics and isolated retina · source_derived_draft · unverified_draft
### sil-no-inotropic-effect Unlike milrinone, sildenafil had no inotropic effects on dog isolated trabeculae carneae so it is unlikely to have the deleterious effects on cardiac function associated with PDE3 inhibitors, while consistent with its mode of action it potentiated the vasorelaxant effects of glyceryl trinitrate on rabbit isolated aortic rings. Condition category: normal nutrient_topic: Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. plain_language: It leaves the heart muscle alone, unlike the drugs that block a different member of the same enzyme family. organism: Human, rabbit and dog tissue_or_cell_type: Corpus cavernosum, aorta, cardiac trabeculae and retina experimental_model: Enzyme selectivity panel with isolated tissue, anaesthetised dog haemodynamics and isolated retina limitations: The single most complete pharmacological characterisation here, covering the target, the absence of effect without upstream drive, the nitrate potentiation, the absence of an inotropic effect, and the retinal effect in one series. exposure: Sildenafil with and without nitric oxide drive, and against glyceryl trinitrate, sodium nitroprusside and milrinone evidence_span: {"source_cache": "artifacts/sildenafil-research/10629850.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "af056c516b44e35eac7b0511ba3a8403ed84c347af6094ebc153f68c8ee7db92", "start_char": 0, "end_char": 2057, "text_sha256": "af056c516b44e35eac7b0511ba3a8403ed84c347af6094ebc153f68c8ee7db92"} [sil-p10629850] The pharmacology of sildenafil, a novel and selective inhibitor of phosphodiesterase (PDE) type 5. (1999). https://pubmed.ncbi.nlm.nih.gov/10629850/ DOI: 10.1254/fpj.114.supplement_22
Complete structured claim and evidence
As a consequence of inhibition of PDE6 in the retina, sildenafil at 1 to 100 micromolar altered the kinetics of the light response of the isolated dog retina and in the anaesthetised dog modified the a-wave and b-wave of the electroretinogram induced by a flash of blue light, effects proportional to plasma concentrations, fully reversible, and occurring only following plasma concentrations approximately 30-fold higher than those active on intracavernosal pressure.
Sildenafil → The electroretinogram a-wave and b-wave source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/sildenafil-research/10629850.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "af056c516b44e35eac7b0511ba3a8403ed84c347af6094ebc153f68c8ee7db92", "start_char": 0, "end_char": 2057, "text_sha256": "af056c516b44e35eac7b0511ba3a8403ed84c347af6094ebc153f68c8ee7db92"}
experimental_model
Enzyme selectivity panel with isolated tissue, anaesthetised dog haemodynamics and isolated retina
exposure
Sildenafil with and without nitric oxide drive, and against glyceryl trinitrate, sodium nitroprusside and milrinone
limitations
The single most complete pharmacological characterisation here, covering the target, the absence of effect without upstream drive, the nitrate potentiation, the absence of an inotropic effect, and the retinal effect in one series.
nutrient_topic
Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. · Sildenafil
organism
Human, rabbit and dog
plain_language
The retinal enzyme is reached too, reversibly, but only at concentrations about thirty times the useful one.
primary_references
[sil-p10629850] The pharmacology of sildenafil, a novel and selective inhibitor of phosphodiesterase (PDE) type 5. (1999). https://pubmed.ncbi.nlm.nih.gov/10629850/ DOI: 10.1254/fpj.114.supplement_22
tissue_or_cell_type
Corpus cavernosum, aorta, cardiac trabeculae and retina
Sildenafil: the enzyme it occupies instead of the substrate, why it cannot start a signal it can only preserve, the organic nitrate interaction that follows from that, the homologous retinal enzyme ten-fold away, and the pulmonary circulation where the same mechanism became a second indication (2026-09-22) · lines 288–299
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Enzyme selectivity panel with isolated tissue, anaesthetised dog haemodynamics and isolated retina · source_derived_draft · unverified_draft
### sil-retinal-effect-at-thirty-fold As a consequence of inhibition of PDE6 in the retina, sildenafil at 1 to 100 micromolar altered the kinetics of the light response of the isolated dog retina and in the anaesthetised dog modified the a-wave and b-wave of the electroretinogram induced by a flash of blue light, effects proportional to plasma concentrations, fully reversible, and occurring only following plasma concentrations approximately 30-fold higher than those active on intracavernosal pressure. Condition category: normal nutrient_topic: Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. plain_language: The retinal enzyme is reached too, reversibly, but only at concentrations about thirty times the useful one. organism: Human, rabbit and dog tissue_or_cell_type: Corpus cavernosum, aorta, cardiac trabeculae and retina experimental_model: Enzyme selectivity panel with isolated tissue, anaesthetised dog haemodynamics and isolated retina limitations: The single most complete pharmacological characterisation here, covering the target, the absence of effect without upstream drive, the nitrate potentiation, the absence of an inotropic effect, and the retinal effect in one series. exposure: Sildenafil with and without nitric oxide drive, and against glyceryl trinitrate, sodium nitroprusside and milrinone evidence_span: {"source_cache": "artifacts/sildenafil-research/10629850.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "af056c516b44e35eac7b0511ba3a8403ed84c347af6094ebc153f68c8ee7db92", "start_char": 0, "end_char": 2057, "text_sha256": "af056c516b44e35eac7b0511ba3a8403ed84c347af6094ebc153f68c8ee7db92"} [sil-p10629850] The pharmacology of sildenafil, a novel and selective inhibitor of phosphodiesterase (PDE) type 5. (1999). https://pubmed.ncbi.nlm.nih.gov/10629850/ DOI: 10.1254/fpj.114.supplement_22
Complete structured claim and evidence
The effects of pelvic nerve stimulation on intracavernosal pressure and penile blood flow were blocked by N-omega-nitro-L-arginine in a dose-related manner confirming the role of nitric oxide, and intravenous sildenafil at 1 to 100 micrograms per kilogram had no direct effect on intracavernosal pressure but potentiated the increase induced by nerve stimulation at plasma concentrations consistent with its relaxation effect on isolated human cavernosal tissue and its inhibition of the enzyme in vitro, with no significant effect on blood pressure or heart rate.
Sildenafil → Intracavernosal pressure source_derived_draftungraded
Experimental context and source evidence
availability_state
biomarker_context Imported condition classification; unverified.
evidence_span
{"source_cache": "artifacts/sildenafil-research/9628657.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "71870b989514f322eb55b17364921cc67de92b3deef59bdf75e2c35db6a97ff7", "start_char": 0, "end_char": 1781, "text_sha256": "71870b989514f322eb55b17364921cc67de92b3deef59bdf75e2c35db6a97ff7"}
experimental_model
Pentobarbital-anaesthetised dogs with pelvic nerve stimulation and nitric oxide synthase inhibition
exposure
Intravenous sildenafil 1 to 100 micrograms per kilogram, with N-omega-nitro-L-arginine
limitations
An in vivo test of the amplifier principle with the nitric oxide synthase inhibitor as the control. Anaesthetised animals.
nutrient_topic
Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. · Sildenafil
organism
Dog
plain_language
In the living animal it raised nothing by itself and roughly doubled what the nerve was already doing.
primary_references
[sil-p9628657] Effect of the selective phosphodiesterase type 5 inhibitor sildenafil on erectile dysfunction in the anesthetized dog. (1998). https://pubmed.ncbi.nlm.nih.gov/9628657/ DOI: 10.1016/s0022-5347(01)63097-0
tissue_or_cell_type
Corpus cavernosum and systemic circulation
trigger_kind
biomarker_context Imported condition classification; unverified.
Sildenafil: the enzyme it occupies instead of the substrate, why it cannot start a signal it can only preserve, the organic nitrate interaction that follows from that, the homologous retinal enzyme ten-fold away, and the pulmonary circulation where the same mechanism became a second indication (2026-09-22) · lines 301–312
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Pentobarbital-anaesthetised dogs with pelvic nerve stimulation and nitric oxide synthase inhibition · source_derived_draft · unverified_draft
### sil-potentiates-only-the-nerve-signal The effects of pelvic nerve stimulation on intracavernosal pressure and penile blood flow were blocked by N-omega-nitro-L-arginine in a dose-related manner confirming the role of nitric oxide, and intravenous sildenafil at 1 to 100 micrograms per kilogram had no direct effect on intracavernosal pressure but potentiated the increase induced by nerve stimulation at plasma concentrations consistent with its relaxation effect on isolated human cavernosal tissue and its inhibition of the enzyme in vitro, with no significant effect on blood pressure or heart rate. Condition category: biomarker_context nutrient_topic: Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. plain_language: In the living animal it raised nothing by itself and roughly doubled what the nerve was already doing. organism: Dog tissue_or_cell_type: Corpus cavernosum and systemic circulation experimental_model: Pentobarbital-anaesthetised dogs with pelvic nerve stimulation and nitric oxide synthase inhibition limitations: An in vivo test of the amplifier principle with the nitric oxide synthase inhibitor as the control. Anaesthetised animals. exposure: Intravenous sildenafil 1 to 100 micrograms per kilogram, with N-omega-nitro-L-arginine evidence_span: {"source_cache": "artifacts/sildenafil-research/9628657.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "71870b989514f322eb55b17364921cc67de92b3deef59bdf75e2c35db6a97ff7", "start_char": 0, "end_char": 1781, "text_sha256": "71870b989514f322eb55b17364921cc67de92b3deef59bdf75e2c35db6a97ff7"} [sil-p9628657] Effect of the selective phosphodiesterase type 5 inhibitor sildenafil on erectile dysfunction in the anesthetized dog. (1998). https://pubmed.ncbi.nlm.nih.gov/9628657/ DOI: 10.1016/s0022-5347(01)63097-0
Complete structured claim and evidence
The major phosphodiesterase activity in the human cardiac ventricle was calcium and calmodulin-dependent PDE1 with no detectable level of PDE5, whereas human saphenous vein contained PDE1, PDE4 and PDE5 and human mesenteric artery contained PDE1, PDE2, PDE3, PDE4 and PDE5, and sildenafil unlike milrinone had no effect on isolated trabeculae carneae, consistent with the lack of PDE5 expression in cardiac myocytes.
Phosphodiesterase 5 family → Human saphenous vein source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/sildenafil-research/10078537.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "dceb60af4400fe67b4ffaf73a0aadb8d2e5fad0966b3372a3e46a91c0e0ccee5", "start_char": 0, "end_char": 2610, "text_sha256": "dceb60af4400fe67b4ffaf73a0aadb8d2e5fad0966b3372a3e46a91c0e0ccee5"}
experimental_model
Immunochemical distribution of phosphodiesterase activity across human tissues with isolated organ bath studies and platelet aggregometry
exposure
Anti-PDE1 and anti-PDE5 antibodies with functional testing, and sildenafil against sodium nitroprusside on platelets
limitations
Maps where the target enzyme is and is not, which is what predicts where the drug acts. Antibody-based detection, so absence of signal is weaker evidence than presence.
nutrient_topic
Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. · Sildenafil
organism
Human, rabbit and dog
plain_language
The target enzyme is in blood vessels and not detectable in heart muscle, which is where the drug does and does not act.
primary_references
[sil-p10078537] Tissue distribution of phosphodiesterase families and the effects of sildenafil on tissue cyclic nucleotides, platelet function, and the contractile responses of trabeculae carneae and aortic rings in vitro. (1999). https://pubmed.ncbi.nlm.nih.gov/10078537/ DOI: 10.1016/s0002-9149(99)00042-9
tissue_or_cell_type
Cardiac ventricle, saphenous vein, mesenteric artery, corpus cavernosum and platelets
Sildenafil: the enzyme it occupies instead of the substrate, why it cannot start a signal it can only preserve, the organic nitrate interaction that follows from that, the homologous retinal enzyme ten-fold away, and the pulmonary circulation where the same mechanism became a second indication (2026-09-22) · lines 314–325
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Immunochemical distribution of phosphodiesterase activity across human tissues with isolated organ bath studies and platelet aggregometry · source_derived_draft · unverified_draft
### sil-no-pde5-in-the-ventricle The major phosphodiesterase activity in the human cardiac ventricle was calcium and calmodulin-dependent PDE1 with no detectable level of PDE5, whereas human saphenous vein contained PDE1, PDE4 and PDE5 and human mesenteric artery contained PDE1, PDE2, PDE3, PDE4 and PDE5, and sildenafil unlike milrinone had no effect on isolated trabeculae carneae, consistent with the lack of PDE5 expression in cardiac myocytes. Condition category: normal nutrient_topic: Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. plain_language: The target enzyme is in blood vessels and not detectable in heart muscle, which is where the drug does and does not act. organism: Human, rabbit and dog tissue_or_cell_type: Cardiac ventricle, saphenous vein, mesenteric artery, corpus cavernosum and platelets experimental_model: Immunochemical distribution of phosphodiesterase activity across human tissues with isolated organ bath studies and platelet aggregometry limitations: Maps where the target enzyme is and is not, which is what predicts where the drug acts. Antibody-based detection, so absence of signal is weaker evidence than presence. exposure: Anti-PDE1 and anti-PDE5 antibodies with functional testing, and sildenafil against sodium nitroprusside on platelets evidence_span: {"source_cache": "artifacts/sildenafil-research/10078537.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "dceb60af4400fe67b4ffaf73a0aadb8d2e5fad0966b3372a3e46a91c0e0ccee5", "start_char": 0, "end_char": 2610, "text_sha256": "dceb60af4400fe67b4ffaf73a0aadb8d2e5fad0966b3372a3e46a91c0e0ccee5"} [sil-p10078537] Tissue distribution of phosphodiesterase families and the effects of sildenafil on tissue cyclic nucleotides, platelet function, and the contractile responses of trabeculae carneae and aortic rings in vitro. (1999). https://pubmed.ncbi.nlm.nih.gov/10078537/ DOI: 10.1016/s0002-9149(99)00042-9
Complete structured claim and evidence
Human platelets were found to contain PDE5 which was inhibited by sildenafil with a half-maximal inhibitory concentration of 6.3 nanomolar consistent with the value in corpus cavernosum, sildenafil alone had no direct effect on platelet function but it potentiated the in vitro antiaggregatory activity of sodium nitroprusside on rabbit and human platelets, and in phenylephrine-contracted rabbit aortic rings it enhanced glyceryl trinitrate relaxation.
Sildenafil → Platelet aggregation source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/sildenafil-research/10078537.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "dceb60af4400fe67b4ffaf73a0aadb8d2e5fad0966b3372a3e46a91c0e0ccee5", "start_char": 0, "end_char": 2610, "text_sha256": "dceb60af4400fe67b4ffaf73a0aadb8d2e5fad0966b3372a3e46a91c0e0ccee5"}
experimental_model
Immunochemical distribution of phosphodiesterase activity across human tissues with isolated organ bath studies and platelet aggregometry
exposure
Anti-PDE1 and anti-PDE5 antibodies with functional testing, and sildenafil against sodium nitroprusside on platelets
limitations
Maps where the target enzyme is and is not, which is what predicts where the drug acts. Antibody-based detection, so absence of signal is weaker evidence than presence.
nutrient_topic
Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. · Sildenafil
organism
Human, rabbit and dog
plain_language
Platelets carry the same enzyme, and again the drug does nothing to them until a nitric oxide donor is present.
primary_references
[sil-p10078537] Tissue distribution of phosphodiesterase families and the effects of sildenafil on tissue cyclic nucleotides, platelet function, and the contractile responses of trabeculae carneae and aortic rings in vitro. (1999). https://pubmed.ncbi.nlm.nih.gov/10078537/ DOI: 10.1016/s0002-9149(99)00042-9
tissue_or_cell_type
Cardiac ventricle, saphenous vein, mesenteric artery, corpus cavernosum and platelets
Sildenafil: the enzyme it occupies instead of the substrate, why it cannot start a signal it can only preserve, the organic nitrate interaction that follows from that, the homologous retinal enzyme ten-fold away, and the pulmonary circulation where the same mechanism became a second indication (2026-09-22) · lines 327–338
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Immunochemical distribution of phosphodiesterase activity across human tissues with isolated organ bath studies and platelet aggregometry · source_derived_draft · unverified_draft
### sil-platelets-need-a-donor-too Human platelets were found to contain PDE5 which was inhibited by sildenafil with a half-maximal inhibitory concentration of 6.3 nanomolar consistent with the value in corpus cavernosum, sildenafil alone had no direct effect on platelet function but it potentiated the in vitro antiaggregatory activity of sodium nitroprusside on rabbit and human platelets, and in phenylephrine-contracted rabbit aortic rings it enhanced glyceryl trinitrate relaxation. Condition category: normal nutrient_topic: Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. plain_language: Platelets carry the same enzyme, and again the drug does nothing to them until a nitric oxide donor is present. organism: Human, rabbit and dog tissue_or_cell_type: Cardiac ventricle, saphenous vein, mesenteric artery, corpus cavernosum and platelets experimental_model: Immunochemical distribution of phosphodiesterase activity across human tissues with isolated organ bath studies and platelet aggregometry limitations: Maps where the target enzyme is and is not, which is what predicts where the drug acts. Antibody-based detection, so absence of signal is weaker evidence than presence. exposure: Anti-PDE1 and anti-PDE5 antibodies with functional testing, and sildenafil against sodium nitroprusside on platelets evidence_span: {"source_cache": "artifacts/sildenafil-research/10078537.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "dceb60af4400fe67b4ffaf73a0aadb8d2e5fad0966b3372a3e46a91c0e0ccee5", "start_char": 0, "end_char": 2610, "text_sha256": "dceb60af4400fe67b4ffaf73a0aadb8d2e5fad0966b3372a3e46a91c0e0ccee5"} [sil-p10078537] Tissue distribution of phosphodiesterase families and the effects of sildenafil on tissue cyclic nucleotides, platelet function, and the contractile responses of trabeculae carneae and aortic rings in vitro. (1999). https://pubmed.ncbi.nlm.nih.gov/10078537/ DOI: 10.1016/s0002-9149(99)00042-9
Complete structured claim and evidence
In human platelet extracts PDE2, PDE3 and PDE5 were identified with no PDE1 or PDE4, cyclic GMP hydrolytic activity was about six times higher than cyclic AMP hydrolytic activity, platelets were among the tissues richest in PDE5, and the selective inhibitor E4021 up to 10 micromolar did not inhibit thromboxane-analogue-induced aggregation on its own while E4021 plus the nitric oxide donor SIN-1, at concentrations that had little effect individually, did inhibit aggregation.
E4021, a selective PDE5 inhibitor → Platelet aggregation source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/sildenafil-research/9115850.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "ff6132fc80fceda8601406e8827a621afbb66fb4ebaf2bcd4f722ac875c73a54", "start_char": 0, "end_char": 1152, "text_sha256": "ff6132fc80fceda8601406e8827a621afbb66fb4ebaf2bcd4f722ac875c73a54"}
experimental_model
Phosphodiesterase isoenzyme separation from human platelet extracts with aggregometry
exposure
A selective PDE5 inhibitor alone and combined with the nitric oxide donor SIN-1
limitations
Establishes the enzyme complement of the platelet and tests whether inhibiting it is sufficient. It uses E4021 rather than sildenafil, which is recorded on the claim.
nutrient_topic
Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. · Sildenafil
organism
Human
plain_language
The tissue richest in this enzyme is unaffected by blocking it unless something is making the messenger.
primary_references
[sil-p9115850] Characterization of the isoenzymes of cyclic nucleotide phosphodiesterase in human platelets and the effects of E4021. (1996). https://pubmed.ncbi.nlm.nih.gov/9115850/ DOI: 10.1016/s0898-6568(96)00112-x
tissue_or_cell_type
Platelets
Sildenafil: the enzyme it occupies instead of the substrate, why it cannot start a signal it can only preserve, the organic nitrate interaction that follows from that, the homologous retinal enzyme ten-fold away, and the pulmonary circulation where the same mechanism became a second indication (2026-09-22) · lines 340–351
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Phosphodiesterase isoenzyme separation from human platelet extracts with aggregometry · source_derived_draft · unverified_draft
### sil-inhibition-alone-is-not-enough In human platelet extracts PDE2, PDE3 and PDE5 were identified with no PDE1 or PDE4, cyclic GMP hydrolytic activity was about six times higher than cyclic AMP hydrolytic activity, platelets were among the tissues richest in PDE5, and the selective inhibitor E4021 up to 10 micromolar did not inhibit thromboxane-analogue-induced aggregation on its own while E4021 plus the nitric oxide donor SIN-1, at concentrations that had little effect individually, did inhibit aggregation. Condition category: normal nutrient_topic: Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. plain_language: The tissue richest in this enzyme is unaffected by blocking it unless something is making the messenger. organism: Human tissue_or_cell_type: Platelets experimental_model: Phosphodiesterase isoenzyme separation from human platelet extracts with aggregometry limitations: Establishes the enzyme complement of the platelet and tests whether inhibiting it is sufficient. It uses E4021 rather than sildenafil, which is recorded on the claim. exposure: A selective PDE5 inhibitor alone and combined with the nitric oxide donor SIN-1 evidence_span: {"source_cache": "artifacts/sildenafil-research/9115850.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "ff6132fc80fceda8601406e8827a621afbb66fb4ebaf2bcd4f722ac875c73a54", "start_char": 0, "end_char": 1152, "text_sha256": "ff6132fc80fceda8601406e8827a621afbb66fb4ebaf2bcd4f722ac875c73a54"} [sil-p9115850] Characterization of the isoenzymes of cyclic nucleotide phosphodiesterase in human platelets and the effects of E4021. (1996). https://pubmed.ncbi.nlm.nih.gov/9115850/ DOI: 10.1016/s0898-6568(96)00112-x
Complete structured claim and evidence
In human penile dorsal arteries and deep dorsal veins sildenafil from 1 nanomolar to 3 micromolar caused concentration-dependent relaxation and amplified the relaxation induced by sodium nitroprusside, and this relaxation was unaffected by the nitric oxide synthase inhibitor NG-monomethyl-L-arginine at 100 micromolar, while electrical field stimulation contractions were attenuated by sildenafil and nitric-oxide-dependent relaxations after guanethidine were enhanced.
Sildenafil → Relaxation of vascular and trabecular smooth muscle source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/sildenafil-research/10962340.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "4bffd4647ca406d3c452e47c7dad6e70ebcc98e4ff4145bc5510b97c38109f1b", "start_char": 0, "end_char": 1577, "text_sha256": "4bffd4647ca406d3c452e47c7dad6e70ebcc98e4ff4145bc5510b97c38109f1b"}
experimental_model
Organ bath studies on penile dorsal arteries and deep dorsal veins from fourteen multiorgan donors
exposure
Sildenafil from 1 nanomolar to 3 micromolar on precontracted vessels, with nitric oxide synthase inhibition and electrical field stimulation
limitations
Tests whether the drug relaxes vessels when nitric oxide synthesis is blocked, and finds that it does. The concentrations reach the micromolar range, well above those active on the enzyme.
nutrient_topic
Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. · Sildenafil
organism
Human
plain_language
In these vessels the drug relaxed them by itself even with nitric oxide synthesis blocked.
primary_references
[sil-p10962340] Effects of sildenafil on human penile blood vessels. (2000). https://pubmed.ncbi.nlm.nih.gov/10962340/ DOI: 10.1016/s0090-4295(00)00622-1
tissue_or_cell_type
Penile blood vessels
Sildenafil: the enzyme it occupies instead of the substrate, why it cannot start a signal it can only preserve, the organic nitrate interaction that follows from that, the homologous retinal enzyme ten-fold away, and the pulmonary circulation where the same mechanism became a second indication (2026-09-22) · lines 353–364
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Organ bath studies on penile dorsal arteries and deep dorsal veins from fourteen multiorgan donors · source_derived_draft · unverified_draft
### sil-direct-relaxation-survives-nos-block In human penile dorsal arteries and deep dorsal veins sildenafil from 1 nanomolar to 3 micromolar caused concentration-dependent relaxation and amplified the relaxation induced by sodium nitroprusside, and this relaxation was unaffected by the nitric oxide synthase inhibitor NG-monomethyl-L-arginine at 100 micromolar, while electrical field stimulation contractions were attenuated by sildenafil and nitric-oxide-dependent relaxations after guanethidine were enhanced. Condition category: normal nutrient_topic: Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. plain_language: In these vessels the drug relaxed them by itself even with nitric oxide synthesis blocked. organism: Human tissue_or_cell_type: Penile blood vessels experimental_model: Organ bath studies on penile dorsal arteries and deep dorsal veins from fourteen multiorgan donors limitations: Tests whether the drug relaxes vessels when nitric oxide synthesis is blocked, and finds that it does. The concentrations reach the micromolar range, well above those active on the enzyme. exposure: Sildenafil from 1 nanomolar to 3 micromolar on precontracted vessels, with nitric oxide synthase inhibition and electrical field stimulation evidence_span: {"source_cache": "artifacts/sildenafil-research/10962340.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "4bffd4647ca406d3c452e47c7dad6e70ebcc98e4ff4145bc5510b97c38109f1b", "start_char": 0, "end_char": 1577, "text_sha256": "4bffd4647ca406d3c452e47c7dad6e70ebcc98e4ff4145bc5510b97c38109f1b"} [sil-p10962340] Effects of sildenafil on human penile blood vessels. (2000). https://pubmed.ncbi.nlm.nih.gov/10962340/ DOI: 10.1016/s0090-4295(00)00622-1
Complete structured claim and evidence
Sildenafil from 10 nanomolar to 30 micromolar caused concentration-dependent relaxation in internal mammary arteries, radial arteries and forearm veins with a modest relaxant effect in coronary arteries, amplified the relaxation induced by sodium nitroprusside in all four vessels, and relaxation was unaffected by the nitric oxide synthase inhibitor NG-monomethyl-L-arginine at 100 micromolar, the drug being eight to ten times more potent than zaprinast.
Sildenafil → Coronary and internal mammary and radial arteries source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/sildenafil-research/11081893.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "7425aaede1777ba3689df435384bb535635a8181487b1937154eb635a01c9dbb", "start_char": 0, "end_char": 1602, "text_sha256": "7425aaede1777ba3689df435384bb535635a8181487b1937154eb635a01c9dbb"}
experimental_model
Organ bath studies on coronary, internal mammary and radial arteries and forearm veins from sixteen multiorgan donors
exposure
Sildenafil from 10 nanomolar to 30 micromolar on precontracted vessels, with nitric oxide synthase inhibition
limitations
Extends the same finding to conduit arteries used in bypass surgery. Again the upper concentrations are far above therapeutic and the relaxation in coronary artery was modest.
nutrient_topic
Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. · Sildenafil
organism
Human
plain_language
The same direct relaxation appears in the arteries used for bypass grafts, and it too survives blocking nitric oxide synthesis.
primary_references
[sil-p11081893] Relaxation induced by cGMP phosphodiesterase inhibitors sildenafil and zaprinast in human vessels. (2000). https://pubmed.ncbi.nlm.nih.gov/11081893/ DOI: 10.1016/s0003-4975(00)01914-7
tissue_or_cell_type
Arterial and venous conduits
Sildenafil: the enzyme it occupies instead of the substrate, why it cannot start a signal it can only preserve, the organic nitrate interaction that follows from that, the homologous retinal enzyme ten-fold away, and the pulmonary circulation where the same mechanism became a second indication (2026-09-22) · lines 366–377
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Organ bath studies on coronary, internal mammary and radial arteries and forearm veins from sixteen multiorgan donors · source_derived_draft · unverified_draft
### sil-conduit-arteries-relax-too Sildenafil from 10 nanomolar to 30 micromolar caused concentration-dependent relaxation in internal mammary arteries, radial arteries and forearm veins with a modest relaxant effect in coronary arteries, amplified the relaxation induced by sodium nitroprusside in all four vessels, and relaxation was unaffected by the nitric oxide synthase inhibitor NG-monomethyl-L-arginine at 100 micromolar, the drug being eight to ten times more potent than zaprinast. Condition category: normal nutrient_topic: Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. plain_language: The same direct relaxation appears in the arteries used for bypass grafts, and it too survives blocking nitric oxide synthesis. organism: Human tissue_or_cell_type: Arterial and venous conduits experimental_model: Organ bath studies on coronary, internal mammary and radial arteries and forearm veins from sixteen multiorgan donors limitations: Extends the same finding to conduit arteries used in bypass surgery. Again the upper concentrations are far above therapeutic and the relaxation in coronary artery was modest. exposure: Sildenafil from 10 nanomolar to 30 micromolar on precontracted vessels, with nitric oxide synthase inhibition evidence_span: {"source_cache": "artifacts/sildenafil-research/11081893.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "7425aaede1777ba3689df435384bb535635a8181487b1937154eb635a01c9dbb", "start_char": 0, "end_char": 1602, "text_sha256": "7425aaede1777ba3689df435384bb535635a8181487b1937154eb635a01c9dbb"} [sil-p11081893] Relaxation induced by cGMP phosphodiesterase inhibitors sildenafil and zaprinast in human vessels. (2000). https://pubmed.ncbi.nlm.nih.gov/11081893/ DOI: 10.1016/s0003-4975(00)01914-7
Complete structured claim and evidence
In haemodynamic studies sildenafil produced small decreases in systemic and pulmonary blood pressure but caused no adverse cardiovascular effects in specific populations of men with coronary heart disease, and it caused no significant changes in coronary blood flow but had a positive effect on coronary flow reserve in men with severe coronary artery disease, suggesting that PDE5 may play an important role in the regulation of coronary blood flow in the healthy and diseased heart, while in retrospective analyses of extensive clinical trials treatment was not associated with any increase in cardiac risk in patients not receiving organic nitrates or nitrate donor drugs.
Sildenafil → Coronary blood flow and coronary flow reserve source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/sildenafil-research/11351772.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "73a1ab2fa66fb9a6155ab7ccae7f405568ffdee07d4a09d61dc106e00c442711", "start_char": 0, "end_char": 1020, "text_sha256": "73a1ab2fa66fb9a6155ab7ccae7f405568ffdee07d4a09d61dc106e00c442711"}
experimental_model
Review of the coronary vascular profile assembled from haemodynamic studies and retrospective analysis of the clinical trial programme
exposure
Sildenafil at therapeutic doses in men with coronary heart disease not taking nitrates
limitations
A review rather than a new study, and the cardiac risk analyses are retrospective. It measures coronary flow in the intact circulation, where the organ bath records cannot.
nutrient_topic
Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. · Sildenafil
organism
Human
plain_language
In the living coronary circulation it did not change resting flow, though it improved the reserve the vessels could call on.
primary_references
[sil-p11351772] Phosphodiesterase 5 inhibition: effects on the coronary vasculature. (2001). https://pubmed.ncbi.nlm.nih.gov/11351772/ DOI: 10.1111/j.1742-1241.2001.tb11011.x
tissue_or_cell_type
Coronary circulation
Sildenafil: the enzyme it occupies instead of the substrate, why it cannot start a signal it can only preserve, the organic nitrate interaction that follows from that, the homologous retinal enzyme ten-fold away, and the pulmonary circulation where the same mechanism became a second indication (2026-09-22) · lines 379–390
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Review of the coronary vascular profile assembled from haemodynamic studies and retrospective analysis of the clinical trial programme · source_derived_draft · unverified_draft
### sil-no-change-in-coronary-flow In haemodynamic studies sildenafil produced small decreases in systemic and pulmonary blood pressure but caused no adverse cardiovascular effects in specific populations of men with coronary heart disease, and it caused no significant changes in coronary blood flow but had a positive effect on coronary flow reserve in men with severe coronary artery disease, suggesting that PDE5 may play an important role in the regulation of coronary blood flow in the healthy and diseased heart, while in retrospective analyses of extensive clinical trials treatment was not associated with any increase in cardiac risk in patients not receiving organic nitrates or nitrate donor drugs. Condition category: normal nutrient_topic: Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. plain_language: In the living coronary circulation it did not change resting flow, though it improved the reserve the vessels could call on. organism: Human tissue_or_cell_type: Coronary circulation experimental_model: Review of the coronary vascular profile assembled from haemodynamic studies and retrospective analysis of the clinical trial programme limitations: A review rather than a new study, and the cardiac risk analyses are retrospective. It measures coronary flow in the intact circulation, where the organ bath records cannot. exposure: Sildenafil at therapeutic doses in men with coronary heart disease not taking nitrates evidence_span: {"source_cache": "artifacts/sildenafil-research/11351772.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "73a1ab2fa66fb9a6155ab7ccae7f405568ffdee07d4a09d61dc106e00c442711", "start_char": 0, "end_char": 1020, "text_sha256": "73a1ab2fa66fb9a6155ab7ccae7f405568ffdee07d4a09d61dc106e00c442711"} [sil-p11351772] Phosphodiesterase 5 inhibition: effects on the coronary vasculature. (2001). https://pubmed.ncbi.nlm.nih.gov/11351772/ DOI: 10.1111/j.1742-1241.2001.tb11011.x
Complete structured claim and evidence
In the concentration range 0.01 to 1 micromolar there was only a minor effect of sildenafil on cyclic GMP levels in isolated human cavernous and cardiac tissues, whereas sildenafil significantly increased cyclic AMP in both at physiologic and supraphysiologic concentrations, more pronounced in cavernous than cardiac tissue, and in the range 0.1 to 1.0 micromolar the effect on cyclic AMP in cardiac samples was almost equivalent to that of milrinone, which the authors offer as a potential mechanism for reported cardiovascular effects and as evidence of cross-talk between the two signalling pathways.
Sildenafil → Cyclic adenosine monophosphate source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/sildenafil-research/10654914.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "95ba66c3ea65d0610adf58e7ab0bca314da8353ecac3f86272c780678929d292", "start_char": 0, "end_char": 1867, "text_sha256": "95ba66c3ea65d0610adf58e7ab0bca314da8353ecac3f86272c780678929d292"}
experimental_model
Radioimmunoassay of cyclic nucleotide accumulation in isolated human corpus cavernosum and cardiac muscle
exposure
Sildenafil from 0.01 to 1 micromolar against sodium nitroprusside, forskolin and milrinone as reference compounds
limitations
Measures both cyclic nucleotides in human tissue with reference compounds for each pathway, and reports an effect on the nucleotide the drug is not supposed to touch. It is an isolated tissue study without added nitric oxide drive.
nutrient_topic
Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. · Sildenafil
organism
Human
plain_language
In this tissue the drug barely moved the messenger it targets and raised the other one instead.
primary_references
[sil-p10654914] Effects of sildenafil on cAMP and cGMP levels in isolated human cavernous and cardiac tissue. (2000). https://pubmed.ncbi.nlm.nih.gov/10654914/ DOI: 10.1016/s0090-4295(99)00371-4
tissue_or_cell_type
Corpus cavernosum and cardiac muscle
Sildenafil: the enzyme it occupies instead of the substrate, why it cannot start a signal it can only preserve, the organic nitrate interaction that follows from that, the homologous retinal enzyme ten-fold away, and the pulmonary circulation where the same mechanism became a second indication (2026-09-22) · lines 392–403
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Radioimmunoassay of cyclic nucleotide accumulation in isolated human corpus cavernosum and cardiac muscle · source_derived_draft · unverified_draft
### sil-cyclic-amp-rose-instead In the concentration range 0.01 to 1 micromolar there was only a minor effect of sildenafil on cyclic GMP levels in isolated human cavernous and cardiac tissues, whereas sildenafil significantly increased cyclic AMP in both at physiologic and supraphysiologic concentrations, more pronounced in cavernous than cardiac tissue, and in the range 0.1 to 1.0 micromolar the effect on cyclic AMP in cardiac samples was almost equivalent to that of milrinone, which the authors offer as a potential mechanism for reported cardiovascular effects and as evidence of cross-talk between the two signalling pathways. Condition category: normal nutrient_topic: Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. plain_language: In this tissue the drug barely moved the messenger it targets and raised the other one instead. organism: Human tissue_or_cell_type: Corpus cavernosum and cardiac muscle experimental_model: Radioimmunoassay of cyclic nucleotide accumulation in isolated human corpus cavernosum and cardiac muscle limitations: Measures both cyclic nucleotides in human tissue with reference compounds for each pathway, and reports an effect on the nucleotide the drug is not supposed to touch. It is an isolated tissue study without added nitric oxide drive. exposure: Sildenafil from 0.01 to 1 micromolar against sodium nitroprusside, forskolin and milrinone as reference compounds evidence_span: {"source_cache": "artifacts/sildenafil-research/10654914.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "95ba66c3ea65d0610adf58e7ab0bca314da8353ecac3f86272c780678929d292", "start_char": 0, "end_char": 1867, "text_sha256": "95ba66c3ea65d0610adf58e7ab0bca314da8353ecac3f86272c780678929d292"} [sil-p10654914] Effects of sildenafil on cAMP and cGMP levels in isolated human cavernous and cardiac tissue. (2000). https://pubmed.ncbi.nlm.nih.gov/10654914/ DOI: 10.1016/s0090-4295(99)00371-4
Complete structured claim and evidence
During treatment with sildenafil 25 milligrams three times daily subjects were significantly less tolerant of intravenously administered glyceryl trinitrate than during placebo based on the occurrence of a greater than 25 millimetre fall in blood pressure or symptomatic hypotension, and when a 500 microgram sublingual glyceryl trinitrate tablet was administered a fourfold greater decrease in systolic blood pressure was observed during the sildenafil period than during placebo, with negligible changes in heart rate, so that administration to patients using organic nitrates in any form is contraindicated.
Sildenafil → Potentiation of the hypotensive effect of an organic nitrate source_derived_draftungraded
Experimental context and source evidence
availability_state
biomarker_context Imported condition classification; unverified.
evidence_span
{"source_cache": "artifacts/sildenafil-research/10078539.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "469d3f90cc5be3f1c0ef247d099fa70d81aa953b8a6b33334abc38d34f346654", "start_char": 0, "end_char": 3999, "text_sha256": "469d3f90cc5be3f1c0ef247d099fa70d81aa953b8a6b33334abc38d34f346654"}
experimental_model
Double-blind placebo-controlled crossover studies of nitrate and calcium antagonist coadministration in healthy men and men with hypertension
exposure
Sildenafil 25 milligrams three times daily with stepwise intravenous and sublingual glyceryl trinitrate, and a single 100 milligram dose with amlodipine
limitations
The design that establishes the contraindication, and the amlodipine arm is the control that shows it is specific to the shared pathway rather than additive antihypertensive effect.
nutrient_topic
Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. · Sildenafil
organism
Human
plain_language
On this drug a standard nitrate tablet dropped blood pressure four times as far.
primary_references
[sil-p10078539] Sildenafil citrate and blood-pressure-lowering drugs: results of drug interaction studies with an organic nitrate and a calcium antagonist. (1999). https://pubmed.ncbi.nlm.nih.gov/10078539/ DOI: 10.1016/s0002-9149(99)00044-2
tissue_or_cell_type
Systemic circulation
trigger_kind
biomarker_context Imported condition classification; unverified.
Sildenafil: the enzyme it occupies instead of the substrate, why it cannot start a signal it can only preserve, the organic nitrate interaction that follows from that, the homologous retinal enzyme ten-fold away, and the pulmonary circulation where the same mechanism became a second indication (2026-09-22) · lines 405–416
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Double-blind placebo-controlled crossover studies of nitrate and calcium antagonist coadministration in healthy men and men with hypertension · source_derived_draft · unverified_draft
### sil-nitrate-potentiation-fourfold During treatment with sildenafil 25 milligrams three times daily subjects were significantly less tolerant of intravenously administered glyceryl trinitrate than during placebo based on the occurrence of a greater than 25 millimetre fall in blood pressure or symptomatic hypotension, and when a 500 microgram sublingual glyceryl trinitrate tablet was administered a fourfold greater decrease in systolic blood pressure was observed during the sildenafil period than during placebo, with negligible changes in heart rate, so that administration to patients using organic nitrates in any form is contraindicated. Condition category: biomarker_context nutrient_topic: Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. plain_language: On this drug a standard nitrate tablet dropped blood pressure four times as far. organism: Human tissue_or_cell_type: Systemic circulation experimental_model: Double-blind placebo-controlled crossover studies of nitrate and calcium antagonist coadministration in healthy men and men with hypertension limitations: The design that establishes the contraindication, and the amlodipine arm is the control that shows it is specific to the shared pathway rather than additive antihypertensive effect. exposure: Sildenafil 25 milligrams three times daily with stepwise intravenous and sublingual glyceryl trinitrate, and a single 100 milligram dose with amlodipine evidence_span: {"source_cache": "artifacts/sildenafil-research/10078539.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "469d3f90cc5be3f1c0ef247d099fa70d81aa953b8a6b33334abc38d34f346654", "start_char": 0, "end_char": 3999, "text_sha256": "469d3f90cc5be3f1c0ef247d099fa70d81aa953b8a6b33334abc38d34f346654"} [sil-p10078539] Sildenafil citrate and blood-pressure-lowering drugs: results of drug interaction studies with an organic nitrate and a calcium antagonist. (1999). https://pubmed.ncbi.nlm.nih.gov/10078539/ DOI: 10.1016/s0002-9149(99)00044-2
Complete structured claim and evidence
In men with hypertension taking 5 or 10 milligrams daily of amlodipine, whose mechanism of action does not involve the cyclic GMP pathway, coadministration of a single 100 milligram dose of sildenafil did not significantly affect amlodipine pharmacokinetics and produced additive but not synergistic reductions in blood pressure, the differences in mean maximum change from baseline being 8 and 7 millimetres of mercury and comparable to the decrease reported for healthy men taking sildenafil alone.
Amlodipine → Potentiation of the hypotensive effect of an organic nitrate source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/sildenafil-research/10078539.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "469d3f90cc5be3f1c0ef247d099fa70d81aa953b8a6b33334abc38d34f346654", "start_char": 0, "end_char": 3999, "text_sha256": "469d3f90cc5be3f1c0ef247d099fa70d81aa953b8a6b33334abc38d34f346654"}
experimental_model
Double-blind placebo-controlled crossover studies of nitrate and calcium antagonist coadministration in healthy men and men with hypertension
exposure
Sildenafil 25 milligrams three times daily with stepwise intravenous and sublingual glyceryl trinitrate, and a single 100 milligram dose with amlodipine
limitations
The design that establishes the contraindication, and the amlodipine arm is the control that shows it is specific to the shared pathway rather than additive antihypertensive effect.
nutrient_topic
Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. · Sildenafil
organism
Human
plain_language
A blood pressure drug working by another route simply adds; only the ones sharing this pathway multiply.
primary_references
[sil-p10078539] Sildenafil citrate and blood-pressure-lowering drugs: results of drug interaction studies with an organic nitrate and a calcium antagonist. (1999). https://pubmed.ncbi.nlm.nih.gov/10078539/ DOI: 10.1016/s0002-9149(99)00044-2
tissue_or_cell_type
Systemic circulation
Sildenafil: the enzyme it occupies instead of the substrate, why it cannot start a signal it can only preserve, the organic nitrate interaction that follows from that, the homologous retinal enzyme ten-fold away, and the pulmonary circulation where the same mechanism became a second indication (2026-09-22) · lines 418–429
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Double-blind placebo-controlled crossover studies of nitrate and calcium antagonist coadministration in healthy men and men with hypertension · source_derived_draft · unverified_draft
### sil-calcium-antagonist-only-additive In men with hypertension taking 5 or 10 milligrams daily of amlodipine, whose mechanism of action does not involve the cyclic GMP pathway, coadministration of a single 100 milligram dose of sildenafil did not significantly affect amlodipine pharmacokinetics and produced additive but not synergistic reductions in blood pressure, the differences in mean maximum change from baseline being 8 and 7 millimetres of mercury and comparable to the decrease reported for healthy men taking sildenafil alone. Condition category: normal nutrient_topic: Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. plain_language: A blood pressure drug working by another route simply adds; only the ones sharing this pathway multiply. organism: Human tissue_or_cell_type: Systemic circulation experimental_model: Double-blind placebo-controlled crossover studies of nitrate and calcium antagonist coadministration in healthy men and men with hypertension limitations: The design that establishes the contraindication, and the amlodipine arm is the control that shows it is specific to the shared pathway rather than additive antihypertensive effect. exposure: Sildenafil 25 milligrams three times daily with stepwise intravenous and sublingual glyceryl trinitrate, and a single 100 milligram dose with amlodipine evidence_span: {"source_cache": "artifacts/sildenafil-research/10078539.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "469d3f90cc5be3f1c0ef247d099fa70d81aa953b8a6b33334abc38d34f346654", "start_char": 0, "end_char": 3999, "text_sha256": "469d3f90cc5be3f1c0ef247d099fa70d81aa953b8a6b33334abc38d34f346654"} [sil-p10078539] Sildenafil citrate and blood-pressure-lowering drugs: results of drug interaction studies with an organic nitrate and a calcium antagonist. (1999). https://pubmed.ncbi.nlm.nih.gov/10078539/ DOI: 10.1016/s0002-9149(99)00044-2
Complete structured claim and evidence
Sildenafil alone can cause mean peak reductions in systolic and diastolic blood pressure of 10 and 7 millimetres of mercury that are not dose related while heart rate is unchanged, and sildenafil and nitrates both increase cyclic GMP levels in the systemic circulation but at different points along the nitric oxide to cyclic GMP pathway, so the combination is contraindicated because they synergistically potentiate vasodilation; retrospective analysis of concomitant antihypertensive medications did not indicate an increase in adverse events, and concurrent renal or hepatic impairment or CYP3A4 inhibitors could increase systemic exposure.
Sildenafil → Cyclic guanosine monophosphate source_derived_draftungraded
Experimental context and source evidence
availability_state
biomarker_context Imported condition classification; unverified.
evidence_span
{"source_cache": "artifacts/sildenafil-research/10078541.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "e65228d2afaad9ce38dccf42c7279ec6b562746aa27b121bf5e5782f36cbe593", "start_char": 0, "end_char": 2772, "text_sha256": "e65228d2afaad9ce38dccf42c7279ec6b562746aa27b121bf5e5782f36cbe593"}
experimental_model
Review of the cardiovascular profile from the clinical development programme and post-marketing surveillance
exposure
Sildenafil alone and with antihypertensive classes, across clinical trials and spontaneous reports
limitations
A manufacturer-authored review of the development programme rather than an independent analysis, and the post-marketing comparisons are retrospective.
nutrient_topic
Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. · Sildenafil
organism
Human
plain_language
Both act on the same pathway at different points, which is why together they multiply rather than add.
primary_references
[sil-p10078541] Overall cardiovascular profile of sildenafil citrate. (1999). https://pubmed.ncbi.nlm.nih.gov/10078541/ DOI: 10.1016/s0002-9149(99)00046-6
tissue_or_cell_type
Cardiovascular system
trigger_kind
biomarker_context Imported condition classification; unverified.
Sildenafil: the enzyme it occupies instead of the substrate, why it cannot start a signal it can only preserve, the organic nitrate interaction that follows from that, the homologous retinal enzyme ten-fold away, and the pulmonary circulation where the same mechanism became a second indication (2026-09-22) · lines 431–442
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Review of the cardiovascular profile from the clinical development programme and post-marketing surveillance · source_derived_draft · unverified_draft
### sil-two-points-on-one-pathway Sildenafil alone can cause mean peak reductions in systolic and diastolic blood pressure of 10 and 7 millimetres of mercury that are not dose related while heart rate is unchanged, and sildenafil and nitrates both increase cyclic GMP levels in the systemic circulation but at different points along the nitric oxide to cyclic GMP pathway, so the combination is contraindicated because they synergistically potentiate vasodilation; retrospective analysis of concomitant antihypertensive medications did not indicate an increase in adverse events, and concurrent renal or hepatic impairment or CYP3A4 inhibitors could increase systemic exposure. Condition category: biomarker_context nutrient_topic: Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. plain_language: Both act on the same pathway at different points, which is why together they multiply rather than add. organism: Human tissue_or_cell_type: Cardiovascular system experimental_model: Review of the cardiovascular profile from the clinical development programme and post-marketing surveillance limitations: A manufacturer-authored review of the development programme rather than an independent analysis, and the post-marketing comparisons are retrospective. exposure: Sildenafil alone and with antihypertensive classes, across clinical trials and spontaneous reports evidence_span: {"source_cache": "artifacts/sildenafil-research/10078541.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "e65228d2afaad9ce38dccf42c7279ec6b562746aa27b121bf5e5782f36cbe593", "start_char": 0, "end_char": 2772, "text_sha256": "e65228d2afaad9ce38dccf42c7279ec6b562746aa27b121bf5e5782f36cbe593"} [sil-p10078541] Overall cardiovascular profile of sildenafil citrate. (1999). https://pubmed.ncbi.nlm.nih.gov/10078541/ DOI: 10.1016/s0002-9149(99)00046-6
Complete structured claim and evidence
In man absorption from the gastrointestinal tract was essentially complete with time to maximum concentration at approximately one hour or less, bioavailability was attenuated by pre-systemic hepatic metabolism in all species, the elimination half-life in man was 3.7 hours, the majority of radioactivity was excreted in faeces with no unchanged drug detected in human excreta, five principal metabolic pathways operated in all species including piperazine N-demethylation, and following oral doses the areas under the curve for the piperazine N-desmethyl and N,N-desethyl metabolites were 55 and 27% that of the parent compound.
Sildenafil → N-desmethyl sildenafil / UK-103,320 source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/sildenafil-research/10219969.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "e8a54758a045a866a0807663e835df338d7b9d650790d7202426425ce056eb58", "start_char": 0, "end_char": 1621, "text_sha256": "e8a54758a045a866a0807663e835df338d7b9d650790d7202426425ce056eb58"}
experimental_model
Pharmacokinetics after single intravenous and oral doses of labelled and unlabelled drug across five species
exposure
Carbon-14 labelled sildenafil with excretion balance and metabolite profiling
limitations
Cross-species pharmacokinetics with a mass balance. Single doses.
nutrient_topic
Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. · Sildenafil
organism
Mouse, rat, rabbit, dog and human
plain_language
It is absorbed completely, cut down by the liver on the way through, and the main breakdown product reaches about half the parent exposure.
primary_references
[sil-p10219969] Pharmacokinetics and metabolism of sildenafil in mouse, rat, rabbit, dog and man. (1999). https://pubmed.ncbi.nlm.nih.gov/10219969/ DOI: 10.1080/004982599238687
tissue_or_cell_type
Whole body
Sildenafil: the enzyme it occupies instead of the substrate, why it cannot start a signal it can only preserve, the organic nitrate interaction that follows from that, the homologous retinal enzyme ten-fold away, and the pulmonary circulation where the same mechanism became a second indication (2026-09-22) · lines 444–455
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Pharmacokinetics after single intravenous and oral doses of labelled and unlabelled drug across five species · source_derived_draft · unverified_draft
### sil-handling-and-metabolites In man absorption from the gastrointestinal tract was essentially complete with time to maximum concentration at approximately one hour or less, bioavailability was attenuated by pre-systemic hepatic metabolism in all species, the elimination half-life in man was 3.7 hours, the majority of radioactivity was excreted in faeces with no unchanged drug detected in human excreta, five principal metabolic pathways operated in all species including piperazine N-demethylation, and following oral doses the areas under the curve for the piperazine N-desmethyl and N,N-desethyl metabolites were 55 and 27% that of the parent compound. Condition category: normal nutrient_topic: Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. plain_language: It is absorbed completely, cut down by the liver on the way through, and the main breakdown product reaches about half the parent exposure. organism: Mouse, rat, rabbit, dog and human tissue_or_cell_type: Whole body experimental_model: Pharmacokinetics after single intravenous and oral doses of labelled and unlabelled drug across five species limitations: Cross-species pharmacokinetics with a mass balance. Single doses. exposure: Carbon-14 labelled sildenafil with excretion balance and metabolite profiling evidence_span: {"source_cache": "artifacts/sildenafil-research/10219969.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "e8a54758a045a866a0807663e835df338d7b9d650790d7202426425ce056eb58", "start_char": 0, "end_char": 1621, "text_sha256": "e8a54758a045a866a0807663e835df338d7b9d650790d7202426425ce056eb58"} [sil-p10219969] Pharmacokinetics and metabolism of sildenafil in mouse, rat, rabbit, dog and man. (1999). https://pubmed.ncbi.nlm.nih.gov/10219969/ DOI: 10.1080/004982599238687
Complete structured claim and evidence
Formation of the major circulating metabolite in human liver microsomes had a Michaelis constant of 14.4 micromolar, of the chemical inhibitors screened only ketoconazole showed detectable inhibition, biotransformation was inhibited by ketoconazole and ritonavir with half-maximal concentrations below 0.02 micromolar, and using microsomes containing cDNA-expressed cytochromes the reaction was mediated by CYP3A4, CYP2C9, CYP2C19 and CYP2D6 with estimated relative contributions to net intrinsic clearance of 79% for CYP3A4 and 20% for CYP2C9 and less than 2% for the other two.
Human cytochrome P450 3A4 → Sildenafil source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_span
{"source_cache": "artifacts/sildenafil-research/10725306.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "21d73da8afc20cb90f2aa2d9bafe7bdbefd7d07037ffb493681414b09154f6d6", "start_char": 0, "end_char": 1190, "text_sha256": "21d73da8afc20cb90f2aa2d9bafe7bdbefd7d07037ffb493681414b09154f6d6"}
experimental_model
In vitro biotransformation in human liver microsomes and microsomes containing heterologously expressed cytochromes
exposure
Formation of the major circulating metabolite with chemical inhibitors and cDNA-expressed cytochromes
limitations
Assigns the clearance quantitatively across cytochromes and identifies the inhibitors that matter. In vitro microsomes.
nutrient_topic
Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. · Sildenafil
organism
Human
plain_language
Four fifths of the clearance runs through one enzyme, so anything blocking that enzyme raises the level of the drug.
primary_references
[sil-p10725306] In vitro biotransformation of sildenafil (Viagra): identification of human cytochromes and potential drug interactions. (2000). https://pubmed.ncbi.nlm.nih.gov/10725306/ DOI: 10.1016/s0090-9556(24)15055-6
tissue_or_cell_type
Liver microsomes
trigger_kind
machinery_impairment Imported condition classification; unverified.
Sildenafil: the enzyme it occupies instead of the substrate, why it cannot start a signal it can only preserve, the organic nitrate interaction that follows from that, the homologous retinal enzyme ten-fold away, and the pulmonary circulation where the same mechanism became a second indication (2026-09-22) · lines 457–468
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · In vitro biotransformation in human liver microsomes and microsomes containing heterologously expressed cytochromes · source_derived_draft · unverified_draft
### sil-cyp3a4-carries-the-clearance Formation of the major circulating metabolite in human liver microsomes had a Michaelis constant of 14.4 micromolar, of the chemical inhibitors screened only ketoconazole showed detectable inhibition, biotransformation was inhibited by ketoconazole and ritonavir with half-maximal concentrations below 0.02 micromolar, and using microsomes containing cDNA-expressed cytochromes the reaction was mediated by CYP3A4, CYP2C9, CYP2C19 and CYP2D6 with estimated relative contributions to net intrinsic clearance of 79% for CYP3A4 and 20% for CYP2C9 and less than 2% for the other two. Condition category: machinery_impairment nutrient_topic: Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. plain_language: Four fifths of the clearance runs through one enzyme, so anything blocking that enzyme raises the level of the drug. organism: Human tissue_or_cell_type: Liver microsomes experimental_model: In vitro biotransformation in human liver microsomes and microsomes containing heterologously expressed cytochromes limitations: Assigns the clearance quantitatively across cytochromes and identifies the inhibitors that matter. In vitro microsomes. exposure: Formation of the major circulating metabolite with chemical inhibitors and cDNA-expressed cytochromes evidence_span: {"source_cache": "artifacts/sildenafil-research/10725306.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "21d73da8afc20cb90f2aa2d9bafe7bdbefd7d07037ffb493681414b09154f6d6", "start_char": 0, "end_char": 1190, "text_sha256": "21d73da8afc20cb90f2aa2d9bafe7bdbefd7d07037ffb493681414b09154f6d6"} [sil-p10725306] In vitro biotransformation of sildenafil (Viagra): identification of human cytochromes and potential drug interactions. (2000). https://pubmed.ncbi.nlm.nih.gov/10725306/ DOI: 10.1016/s0090-9556(24)15055-6
Complete structured claim and evidence
In six HIV-infected patients at steady state on indinavir a single 25 milligram dose of sildenafil did not significantly alter plasma indinavir concentrations, but the geometric mean area under the sildenafil concentration curve of 1631 nanograms per millilitre hour was 4.4 times higher than data from historical controls given either 50 or 100 milligrams and dose normalised to 25 milligrams, and in a parallel study indinavir was a potent inhibitor of sildenafil hepatic metabolism in vitro with a half-maximal inhibitory concentration of 0.39 micromolar, so that the mechanism of the increase is inhibition of hepatic metabolism and a lower starting dose may be more appropriate in this setting.
Indinavir → Sildenafil source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_span
{"source_cache": "artifacts/sildenafil-research/10546851.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "a789c249a680590fd363d884785a531062441be8e2442ec872fa832dc43b7504", "start_char": 0, "end_char": 2556, "text_sha256": "a789c249a680590fd363d884785a531062441be8e2442ec872fa832dc43b7504"}
experimental_model
Open pharmacokinetic study in six patients at steady state on a protease inhibitor, with a parallel in vitro metabolism arm
exposure
A single 25 milligram dose of sildenafil added to steady-state indinavir, with plasma sampling to eight hours
limitations
Six patients and no concurrent control group: the sildenafil exposure is compared with dose-normalised historical controls rather than with the same patients off indinavir.
nutrient_topic
Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. · Sildenafil
organism
Human
plain_language
A drug that blocks the same liver enzyme left more than four times as much of it in the blood.
primary_references
[sil-p10546851] Interaction of sildenafil and indinavir when co-administered to HIV-positive patients. (1999). https://pubmed.ncbi.nlm.nih.gov/10546851/ DOI: 10.1097/00002030-199910220-00001
tissue_or_cell_type
Systemic circulation and liver microsomes
trigger_kind
machinery_impairment Imported condition classification; unverified.
Sildenafil: the enzyme it occupies instead of the substrate, why it cannot start a signal it can only preserve, the organic nitrate interaction that follows from that, the homologous retinal enzyme ten-fold away, and the pulmonary circulation where the same mechanism became a second indication (2026-09-22) · lines 470–481
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Open pharmacokinetic study in six patients at steady state on a protease inhibitor, with a parallel in vitro metabolism arm · source_derived_draft · unverified_draft
### sil-protease-inhibitor-quadruples-exposure In six HIV-infected patients at steady state on indinavir a single 25 milligram dose of sildenafil did not significantly alter plasma indinavir concentrations, but the geometric mean area under the sildenafil concentration curve of 1631 nanograms per millilitre hour was 4.4 times higher than data from historical controls given either 50 or 100 milligrams and dose normalised to 25 milligrams, and in a parallel study indinavir was a potent inhibitor of sildenafil hepatic metabolism in vitro with a half-maximal inhibitory concentration of 0.39 micromolar, so that the mechanism of the increase is inhibition of hepatic metabolism and a lower starting dose may be more appropriate in this setting. Condition category: machinery_impairment nutrient_topic: Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. plain_language: A drug that blocks the same liver enzyme left more than four times as much of it in the blood. organism: Human tissue_or_cell_type: Systemic circulation and liver microsomes experimental_model: Open pharmacokinetic study in six patients at steady state on a protease inhibitor, with a parallel in vitro metabolism arm limitations: Six patients and no concurrent control group: the sildenafil exposure is compared with dose-normalised historical controls rather than with the same patients off indinavir. exposure: A single 25 milligram dose of sildenafil added to steady-state indinavir, with plasma sampling to eight hours evidence_span: {"source_cache": "artifacts/sildenafil-research/10546851.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "a789c249a680590fd363d884785a531062441be8e2442ec872fa832dc43b7504", "start_char": 0, "end_char": 2556, "text_sha256": "a789c249a680590fd363d884785a531062441be8e2442ec872fa832dc43b7504"} [sil-p10546851] Interaction of sildenafil and indinavir when co-administered to HIV-positive patients. (1999). https://pubmed.ncbi.nlm.nih.gov/10546851/ DOI: 10.1097/00002030-199910220-00001
Complete structured claim and evidence
Sildenafil has a mild inhibitory effect on PDE6, which controls the level of cyclic guanosine monophosphate in the retina, and it may cause a perception of bluish haze or increased light sensitivity in some patients, with long-term retinal damage not reported although long-term electroretinographic studies have not been performed; the drug causes a mild lowering of blood pressure and is contraindicated in patients taking any form of nitrate medication.
Sildenafil → Transient colour vision disturbance and increased light sensitivity source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/sildenafil-research/10541153.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "8c5d3c6e9d606690e6cc997086ded515a4e9f785561a7fc58fdbfb75b3f0a79a", "start_char": 0, "end_char": 1024, "text_sha256": "8c5d3c6e9d606690e6cc997086ded515a4e9f785561a7fc58fdbfb75b3f0a79a"}
experimental_model
Review of the ophthalmic profile shortly after marketing approval
exposure
Reported visual effects at therapeutic doses
limitations
A short review written in the first year of marketing. It records explicitly that long-term electroretinographic studies had not been performed, which is the limitation that matters for the claim.
nutrient_topic
Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. · Sildenafil
organism
Human
plain_language
The colour disturbance some people notice is the same drug reaching the retinal version of the enzyme.
primary_references
[sil-p10541153] Sildenafil (Viagra) and ophthalmology. (1999). https://pubmed.ncbi.nlm.nih.gov/10541153/ DOI: 10.1016/s0039-6257(99)00079-x
tissue_or_cell_type
Retina
Sildenafil: the enzyme it occupies instead of the substrate, why it cannot start a signal it can only preserve, the organic nitrate interaction that follows from that, the homologous retinal enzyme ten-fold away, and the pulmonary circulation where the same mechanism became a second indication (2026-09-22) · lines 483–494
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Review of the ophthalmic profile shortly after marketing approval · source_derived_draft · unverified_draft
### sil-transient-visual-disturbance Sildenafil has a mild inhibitory effect on PDE6, which controls the level of cyclic guanosine monophosphate in the retina, and it may cause a perception of bluish haze or increased light sensitivity in some patients, with long-term retinal damage not reported although long-term electroretinographic studies have not been performed; the drug causes a mild lowering of blood pressure and is contraindicated in patients taking any form of nitrate medication. Condition category: normal nutrient_topic: Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. plain_language: The colour disturbance some people notice is the same drug reaching the retinal version of the enzyme. organism: Human tissue_or_cell_type: Retina experimental_model: Review of the ophthalmic profile shortly after marketing approval limitations: A short review written in the first year of marketing. It records explicitly that long-term electroretinographic studies had not been performed, which is the limitation that matters for the claim. exposure: Reported visual effects at therapeutic doses evidence_span: {"source_cache": "artifacts/sildenafil-research/10541153.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "8c5d3c6e9d606690e6cc997086ded515a4e9f785561a7fc58fdbfb75b3f0a79a", "start_char": 0, "end_char": 1024, "text_sha256": "8c5d3c6e9d606690e6cc997086ded515a4e9f785561a7fc58fdbfb75b3f0a79a"} [sil-p10541153] Sildenafil (Viagra) and ophthalmology. (1999). https://pubmed.ncbi.nlm.nih.gov/10541153/ DOI: 10.1016/s0039-6257(99)00079-x
Complete structured claim and evidence
Early in development it was noted that besides its major inhibitory effect on the intended target, the vascular-associated PDE5, the drug also exerts a lesser but definite inhibitory effect on the closely related PDE6 located in the retina, and for this reason preclinical evaluation included electroretinography plus postmortem histology and an extended eye examination was incorporated into clinical protocols, with data on the incidence, duration and type of colour vision defects observed at different doses.
Structural homology between phosphodiesterase type 5 and rod phosphodiesterase 6 → Transient colour vision disturbance and increased light sensitivity source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/sildenafil-research/10703120.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "fc004205f7e036cf52e469c5f9941c4f69d216a012ccd8a588052b950c1077e6", "start_char": 0, "end_char": 2146, "text_sha256": "fc004205f7e036cf52e469c5f9941c4f69d216a012ccd8a588052b950c1077e6"}
experimental_model
Review of how the ocular safety profile was established from preclinical work through to post-marketing surveillance
exposure
Electroretinography and histology in preclinical evaluation, with extended eye examination in clinical protocols and registry surveillance
limitations
A methodological review of how the signal was tracked rather than a new measurement. It is useful because it records that the retinal effect was predicted before it was looked for.
nutrient_topic
Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. · Sildenafil
organism
Human and animal
plain_language
The visual effect was not a surprise; the homology between the two enzymes predicted it and the trials were designed to look for it.
primary_references
[sil-p10703120] Ocular safety of Viagra, (sildenafil citrate). (1999). https://pubmed.ncbi.nlm.nih.gov/10703120/
tissue_or_cell_type
Retina
Sildenafil: the enzyme it occupies instead of the substrate, why it cannot start a signal it can only preserve, the organic nitrate interaction that follows from that, the homologous retinal enzyme ten-fold away, and the pulmonary circulation where the same mechanism became a second indication (2026-09-22) · lines 496–507
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Review of how the ocular safety profile was established from preclinical work through to post-marketing surveillance · source_derived_draft · unverified_draft
### sil-the-off-target-was-predicted Early in development it was noted that besides its major inhibitory effect on the intended target, the vascular-associated PDE5, the drug also exerts a lesser but definite inhibitory effect on the closely related PDE6 located in the retina, and for this reason preclinical evaluation included electroretinography plus postmortem histology and an extended eye examination was incorporated into clinical protocols, with data on the incidence, duration and type of colour vision defects observed at different doses. Condition category: normal nutrient_topic: Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. plain_language: The visual effect was not a surprise; the homology between the two enzymes predicted it and the trials were designed to look for it. organism: Human and animal tissue_or_cell_type: Retina experimental_model: Review of how the ocular safety profile was established from preclinical work through to post-marketing surveillance limitations: A methodological review of how the signal was tracked rather than a new measurement. It is useful because it records that the retinal effect was predicted before it was looked for. exposure: Electroretinography and histology in preclinical evaluation, with extended eye examination in clinical protocols and registry surveillance evidence_span: {"source_cache": "artifacts/sildenafil-research/10703120.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "fc004205f7e036cf52e469c5f9941c4f69d216a012ccd8a588052b950c1077e6", "start_char": 0, "end_char": 2146, "text_sha256": "fc004205f7e036cf52e469c5f9941c4f69d216a012ccd8a588052b950c1077e6"} [sil-p10703120] Ocular safety of Viagra, (sildenafil citrate). (1999). https://pubmed.ncbi.nlm.nih.gov/10703120/
Complete structured claim and evidence
In isolated perfused lung of wild-type and endothelial nitric oxide synthase deficient mice sildenafil markedly blunted acute hypoxic pulmonary vasoconstriction, wild-type mice dosed through three weeks of hypoxia showed a significant reduction in right ventricular systolic pressure from 43.3 to 29.9 millimetres of mercury coupled with a small reduction in right ventricular hypertrophy and inhibition of pulmonary vascular remodelling, while in the knockout mice the drug attenuated the rise in right ventricular systolic pressure but without significant effect on hypertrophy or remodelling, so the endothelial pathway contributes but other biochemical sources of cyclic GMP also play a role.
Sildenafil → Hypoxic pulmonary vasoconstriction source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_span
{"source_cache": "artifacts/sildenafil-research/11468204.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "41d880663288811422c4400d86de1eedd4d5b254d8bb3a59a8fbff01dedbcb24", "start_char": 0, "end_char": 1820, "text_sha256": "41d880663288811422c4400d86de1eedd4d5b254d8bb3a59a8fbff01dedbcb24"}
experimental_model
Randomised double-blind hypoxic challenge in ten volunteers with right heart catheterisation, plus isolated perfused lung and chronic hypoxia in wild-type and endothelial nitric oxide synthase deficient mice
exposure
Sildenafil 100 milligrams orally before 11 percent oxygen for 30 minutes, and 25 milligrams per kilogram daily through three weeks of 10 percent oxygen in mice
limitations
The knockout arm is what makes this decisive about the source of cyclic GMP, and the human arm measures pressure invasively. Ten volunteers, and the mouse exposure is far longer than the human one.
nutrient_topic
Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. · Sildenafil
organism
Mouse
plain_language
It still works when the main source of the upstream signal has been deleted, so something else is supplying the messenger.
primary_references
[sil-p11468204] Sildenafil inhibits hypoxia-induced pulmonary hypertension. (2001). https://pubmed.ncbi.nlm.nih.gov/11468204/ DOI: 10.1161/hc2901.093117
tissue_or_cell_type
Pulmonary circulation
trigger_kind
machinery_impairment Imported condition classification; unverified.
Sildenafil: the enzyme it occupies instead of the substrate, why it cannot start a signal it can only preserve, the organic nitrate interaction that follows from that, the homologous retinal enzyme ten-fold away, and the pulmonary circulation where the same mechanism became a second indication (2026-09-22) · lines 509–520
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Randomised double-blind hypoxic challenge in ten volunteers with right heart catheterisation, plus isolated perfused lung and chronic hypoxia in wild-type and endothelial nitric oxide synthase deficient mice · source_derived_draft · unverified_draft
### sil-works-without-enos In isolated perfused lung of wild-type and endothelial nitric oxide synthase deficient mice sildenafil markedly blunted acute hypoxic pulmonary vasoconstriction, wild-type mice dosed through three weeks of hypoxia showed a significant reduction in right ventricular systolic pressure from 43.3 to 29.9 millimetres of mercury coupled with a small reduction in right ventricular hypertrophy and inhibition of pulmonary vascular remodelling, while in the knockout mice the drug attenuated the rise in right ventricular systolic pressure but without significant effect on hypertrophy or remodelling, so the endothelial pathway contributes but other biochemical sources of cyclic GMP also play a role. Condition category: machinery_impairment nutrient_topic: Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. plain_language: It still works when the main source of the upstream signal has been deleted, so something else is supplying the messenger. organism: Mouse tissue_or_cell_type: Pulmonary circulation experimental_model: Randomised double-blind hypoxic challenge in ten volunteers with right heart catheterisation, plus isolated perfused lung and chronic hypoxia in wild-type and endothelial nitric oxide synthase deficient mice limitations: The knockout arm is what makes this decisive about the source of cyclic GMP, and the human arm measures pressure invasively. Ten volunteers, and the mouse exposure is far longer than the human one. exposure: Sildenafil 100 milligrams orally before 11 percent oxygen for 30 minutes, and 25 milligrams per kilogram daily through three weeks of 10 percent oxygen in mice evidence_span: {"source_cache": "artifacts/sildenafil-research/11468204.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "41d880663288811422c4400d86de1eedd4d5b254d8bb3a59a8fbff01dedbcb24", "start_char": 0, "end_char": 1820, "text_sha256": "41d880663288811422c4400d86de1eedd4d5b254d8bb3a59a8fbff01dedbcb24"} [sil-p11468204] Sildenafil inhibits hypoxia-induced pulmonary hypertension. (2001). https://pubmed.ncbi.nlm.nih.gov/11468204/ DOI: 10.1161/hc2901.093117
Complete structured claim and evidence
In a randomised double-blind study the acute 56% increase in mean pulmonary artery pressure produced by breathing 11 percent oxygen during placebo treatment, from 16.0 to 25.0 millimetres of mercury, was almost abolished by sildenafil 100 milligrams, from 16.0 to 18.0 millimetres of mercury, with no significant effect on systemic blood pressure.
Sildenafil → Mean or systolic pulmonary artery pressure source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/sildenafil-research/11468204.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "41d880663288811422c4400d86de1eedd4d5b254d8bb3a59a8fbff01dedbcb24", "start_char": 0, "end_char": 1820, "text_sha256": "41d880663288811422c4400d86de1eedd4d5b254d8bb3a59a8fbff01dedbcb24"}
experimental_model
Randomised double-blind hypoxic challenge in ten volunteers with right heart catheterisation, plus isolated perfused lung and chronic hypoxia in wild-type and endothelial nitric oxide synthase deficient mice
exposure
Sildenafil 100 milligrams orally before 11 percent oxygen for 30 minutes, and 25 milligrams per kilogram daily through three weeks of 10 percent oxygen in mice
limitations
The knockout arm is what makes this decisive about the source of cyclic GMP, and the human arm measures pressure invasively. Ten volunteers, and the mouse exposure is far longer than the human one.
nutrient_topic
Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. · Sildenafil
organism
Human and mouse
plain_language
A single dose almost removed the pressure rise that low oxygen causes in the lung, without touching pressure elsewhere.
primary_references
[sil-p11468204] Sildenafil inhibits hypoxia-induced pulmonary hypertension. (2001). https://pubmed.ncbi.nlm.nih.gov/11468204/ DOI: 10.1161/hc2901.093117
tissue_or_cell_type
Pulmonary circulation
Sildenafil: the enzyme it occupies instead of the substrate, why it cannot start a signal it can only preserve, the organic nitrate interaction that follows from that, the homologous retinal enzyme ten-fold away, and the pulmonary circulation where the same mechanism became a second indication (2026-09-22) · lines 522–533
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Randomised double-blind hypoxic challenge in ten volunteers with right heart catheterisation, plus isolated perfused lung and chronic hypoxia in wild-type and endothelial nitric oxide synthase deficient mice · source_derived_draft · unverified_draft
### sil-abolishes-the-hypoxic-rise In a randomised double-blind study the acute 56% increase in mean pulmonary artery pressure produced by breathing 11 percent oxygen during placebo treatment, from 16.0 to 25.0 millimetres of mercury, was almost abolished by sildenafil 100 milligrams, from 16.0 to 18.0 millimetres of mercury, with no significant effect on systemic blood pressure. Condition category: normal nutrient_topic: Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. plain_language: A single dose almost removed the pressure rise that low oxygen causes in the lung, without touching pressure elsewhere. organism: Human and mouse tissue_or_cell_type: Pulmonary circulation experimental_model: Randomised double-blind hypoxic challenge in ten volunteers with right heart catheterisation, plus isolated perfused lung and chronic hypoxia in wild-type and endothelial nitric oxide synthase deficient mice limitations: The knockout arm is what makes this decisive about the source of cyclic GMP, and the human arm measures pressure invasively. Ten volunteers, and the mouse exposure is far longer than the human one. exposure: Sildenafil 100 milligrams orally before 11 percent oxygen for 30 minutes, and 25 milligrams per kilogram daily through three weeks of 10 percent oxygen in mice evidence_span: {"source_cache": "artifacts/sildenafil-research/11468204.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "41d880663288811422c4400d86de1eedd4d5b254d8bb3a59a8fbff01dedbcb24", "start_char": 0, "end_char": 1820, "text_sha256": "41d880663288811422c4400d86de1eedd4d5b254d8bb3a59a8fbff01dedbcb24"} [sil-p11468204] Sildenafil inhibits hypoxia-induced pulmonary hypertension. (2001). https://pubmed.ncbi.nlm.nih.gov/11468204/ DOI: 10.1161/hc2901.093117
Complete structured claim and evidence
In thirteen patients with severe pulmonary hypertension the decrease in pulmonary vascular resistance was similar with inhaled nitric oxide at 19% and sildenafil at 27% while the combination was more effective than inhaled nitric oxide alone at 32%, sildenafil and the combination increased cardiac index by 17% whereas inhaled nitric oxide did not, inhaled nitric oxide increased whereas sildenafil tended to decrease pulmonary capillary wedge pressure, systemic arterial pressure was similar among groups and did not decrease, and cyclic GMP rose similarly with each agent while the combination raised it synergistically.
Sildenafil → Pulmonary vascular resistance source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/sildenafil-research/12021227.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "69f5687bcf1bb0fcf9d96eb7fe2f756ccfe3bbdd76af85560110b985245947e0", "start_char": 0, "end_char": 1828, "text_sha256": "69f5687bcf1bb0fcf9d96eb7fe2f756ccfe3bbdd76af85560110b985245947e0"}
experimental_model
Acute haemodynamic study in thirteen consecutive patients referred for transplantation assessment or therapy guidance
exposure
Inhaled nitric oxide at 80 parts per million, oral sildenafil 75 milligrams, and the combination, with serum cyclic GMP measured
limitations
Compares the drug directly against the reference selective pulmonary vasodilator in the same patients and measures the messenger. Thirteen patients and a single dose.
nutrient_topic
Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. · Sildenafil
organism
Human
plain_language
An oral tablet matched inhaled nitric oxide as a selective lung vasodilator and, unlike it, raised cardiac output.
primary_references
[sil-p12021227] Oral sildenafil is an effective and specific pulmonary vasodilator in patients with pulmonary arterial hypertension: comparison with inhaled nitric oxide. (2002). https://pubmed.ncbi.nlm.nih.gov/12021227/ DOI: 10.1161/01.cir.0000016641.12984.dc
tissue_or_cell_type
Pulmonary circulation
Sildenafil: the enzyme it occupies instead of the substrate, why it cannot start a signal it can only preserve, the organic nitrate interaction that follows from that, the homologous retinal enzyme ten-fold away, and the pulmonary circulation where the same mechanism became a second indication (2026-09-22) · lines 535–546
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Acute haemodynamic study in thirteen consecutive patients referred for transplantation assessment or therapy guidance · source_derived_draft · unverified_draft
### sil-as-selective-as-inhaled-no In thirteen patients with severe pulmonary hypertension the decrease in pulmonary vascular resistance was similar with inhaled nitric oxide at 19% and sildenafil at 27% while the combination was more effective than inhaled nitric oxide alone at 32%, sildenafil and the combination increased cardiac index by 17% whereas inhaled nitric oxide did not, inhaled nitric oxide increased whereas sildenafil tended to decrease pulmonary capillary wedge pressure, systemic arterial pressure was similar among groups and did not decrease, and cyclic GMP rose similarly with each agent while the combination raised it synergistically. Condition category: normal nutrient_topic: Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. plain_language: An oral tablet matched inhaled nitric oxide as a selective lung vasodilator and, unlike it, raised cardiac output. organism: Human tissue_or_cell_type: Pulmonary circulation experimental_model: Acute haemodynamic study in thirteen consecutive patients referred for transplantation assessment or therapy guidance limitations: Compares the drug directly against the reference selective pulmonary vasodilator in the same patients and measures the messenger. Thirteen patients and a single dose. exposure: Inhaled nitric oxide at 80 parts per million, oral sildenafil 75 milligrams, and the combination, with serum cyclic GMP measured evidence_span: {"source_cache": "artifacts/sildenafil-research/12021227.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "69f5687bcf1bb0fcf9d96eb7fe2f756ccfe3bbdd76af85560110b985245947e0", "start_char": 0, "end_char": 1828, "text_sha256": "69f5687bcf1bb0fcf9d96eb7fe2f756ccfe3bbdd76af85560110b985245947e0"} [sil-p12021227] Oral sildenafil is an effective and specific pulmonary vasodilator in patients with pulmonary arterial hypertension: comparison with inhaled nitric oxide. (2002). https://pubmed.ncbi.nlm.nih.gov/12021227/ DOI: 10.1161/01.cir.0000016641.12984.dc
Complete structured claim and evidence
Chronic hypoxia decreased RhoA messenger RNA and protein expression in rat main pulmonary artery and abolished RhoA-mediated calcium sensitisation of contraction, accounting for the decreased responses to endothelin-1, noradrenaline and a thromboxane analogue, and treatment with sildenafil at 25 milligrams per kilogram daily throughout the exposure prevented the downregulation of RhoA, the reduction of contraction and the pulmonary artery remodelling, indicating a major role of the nitric oxide and cyclic GMP pathway in the altered RhoA signalling.
Sildenafil → RhoA and Rho-kinase-mediated calcium sensitisation of contraction source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/sildenafil-research/12946946.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "ce3f4a451c01082a280ebffc7e9661ec5667161f4974b39ba15c52fa940754f7", "start_char": 0, "end_char": 1768, "text_sha256": "ce3f4a451c01082a280ebffc7e9661ec5667161f4974b39ba15c52fa940754f7"}
experimental_model
Rat pulmonary artery contractility and RhoA expression after two weeks of chronic hypoxia
exposure
Sildenafil 25 milligrams per kilogram daily through two weeks of 10 percent oxygen, with real-time PCR and western blotting
limitations
Identifies a second arm of the mechanism beyond cyclic-GMP-mediated relaxation. A rat chronic hypoxia model, and the causal chain from cyclic GMP to RhoA expression is inferred rather than dissected.
nutrient_topic
Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. · Sildenafil
organism
Rat
plain_language
Beyond relaxing the vessel, the drug preserved the contractile machinery that chronic low oxygen otherwise degrades.
primary_references
[sil-p12946946] Sildenafil prevents change in RhoA expression induced by chronic hypoxia in rat pulmonary artery. (2003). https://pubmed.ncbi.nlm.nih.gov/12946946/ DOI: 10.1161/01.res.0000093220.90027.d9
tissue_or_cell_type
Pulmonary artery
Sildenafil: the enzyme it occupies instead of the substrate, why it cannot start a signal it can only preserve, the organic nitrate interaction that follows from that, the homologous retinal enzyme ten-fold away, and the pulmonary circulation where the same mechanism became a second indication (2026-09-22) · lines 548–559
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Rat pulmonary artery contractility and RhoA expression after two weeks of chronic hypoxia · source_derived_draft · unverified_draft
### sil-prevents-rhoa-downregulation Chronic hypoxia decreased RhoA messenger RNA and protein expression in rat main pulmonary artery and abolished RhoA-mediated calcium sensitisation of contraction, accounting for the decreased responses to endothelin-1, noradrenaline and a thromboxane analogue, and treatment with sildenafil at 25 milligrams per kilogram daily throughout the exposure prevented the downregulation of RhoA, the reduction of contraction and the pulmonary artery remodelling, indicating a major role of the nitric oxide and cyclic GMP pathway in the altered RhoA signalling. Condition category: normal nutrient_topic: Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. plain_language: Beyond relaxing the vessel, the drug preserved the contractile machinery that chronic low oxygen otherwise degrades. organism: Rat tissue_or_cell_type: Pulmonary artery experimental_model: Rat pulmonary artery contractility and RhoA expression after two weeks of chronic hypoxia limitations: Identifies a second arm of the mechanism beyond cyclic-GMP-mediated relaxation. A rat chronic hypoxia model, and the causal chain from cyclic GMP to RhoA expression is inferred rather than dissected. exposure: Sildenafil 25 milligrams per kilogram daily through two weeks of 10 percent oxygen, with real-time PCR and western blotting evidence_span: {"source_cache": "artifacts/sildenafil-research/12946946.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "ce3f4a451c01082a280ebffc7e9661ec5667161f4974b39ba15c52fa940754f7", "start_char": 0, "end_char": 1768, "text_sha256": "ce3f4a451c01082a280ebffc7e9661ec5667161f4974b39ba15c52fa940754f7"} [sil-p12946946] Sildenafil prevents change in RhoA expression induced by chronic hypoxia in rat pulmonary artery. (2003). https://pubmed.ncbi.nlm.nih.gov/12946946/ DOI: 10.1161/01.res.0000093220.90027.d9
Complete structured claim and evidence
PDE5 immunoreactivity was localized to smooth muscle cells in the medial layer of pulmonary arteries and veins in the normal rat lung and in distal muscularized arteries under 25 micrometres in diameter after hypoxia-induced pulmonary hypertension, sildenafil at 25 or 75 milligrams per kilogram per day given before hypoxia produced marked dose-dependent inhibition in the rise of pulmonary artery pressure of 60 to 90% and a 28.4% reduction in vascular muscularization, and when begun after 14 days of hypoxia it significantly reduced pulmonary artery pressure by 30% and partially reversed pulmonary artery muscularization by 39.9%.
Sildenafil → Pulmonary vascular remodelling source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/sildenafil-research/12796132.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "61d9020b6275a7c57fcee753c74b06c334ad034286eeaccdcbdf12e49b472122", "start_char": 0, "end_char": 1616, "text_sha256": "61d9020b6275a7c57fcee753c74b06c334ad034286eeaccdcbdf12e49b472122"}
experimental_model
Continuous telemetric pulmonary artery pressure measurement with immunolocalisation and morphometry in rats exposed to hypoxia for up to 42 days
exposure
Sildenafil 25 or 75 milligrams per kilogram per day started before hypoxia, or started after 14 days of established pulmonary hypertension
limitations
The delayed-treatment arm is what distinguishes prevention from reversal. A rat hypoxia model, and the reversal of muscularisation is partial.
nutrient_topic
Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. · Sildenafil
organism
Rat
plain_language
Started after the damage was already there, it still pushed the pressure down and partly undid the thickening.
primary_references
[sil-p12796132] Phosphodiesterase type 5 as a target for the treatment of hypoxia-induced pulmonary hypertension. (2003). https://pubmed.ncbi.nlm.nih.gov/12796132/ DOI: 10.1161/01.cir.0000074226.20466.b1
tissue_or_cell_type
Pulmonary vascular tree
Sildenafil: the enzyme it occupies instead of the substrate, why it cannot start a signal it can only preserve, the organic nitrate interaction that follows from that, the homologous retinal enzyme ten-fold away, and the pulmonary circulation where the same mechanism became a second indication (2026-09-22) · lines 561–572
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Continuous telemetric pulmonary artery pressure measurement with immunolocalisation and morphometry in rats exposed to hypoxia for up to 42 days · source_derived_draft · unverified_draft
### sil-reverses-established-remodelling PDE5 immunoreactivity was localized to smooth muscle cells in the medial layer of pulmonary arteries and veins in the normal rat lung and in distal muscularized arteries under 25 micrometres in diameter after hypoxia-induced pulmonary hypertension, sildenafil at 25 or 75 milligrams per kilogram per day given before hypoxia produced marked dose-dependent inhibition in the rise of pulmonary artery pressure of 60 to 90% and a 28.4% reduction in vascular muscularization, and when begun after 14 days of hypoxia it significantly reduced pulmonary artery pressure by 30% and partially reversed pulmonary artery muscularization by 39.9%. Condition category: normal nutrient_topic: Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. plain_language: Started after the damage was already there, it still pushed the pressure down and partly undid the thickening. organism: Rat tissue_or_cell_type: Pulmonary vascular tree experimental_model: Continuous telemetric pulmonary artery pressure measurement with immunolocalisation and morphometry in rats exposed to hypoxia for up to 42 days limitations: The delayed-treatment arm is what distinguishes prevention from reversal. A rat hypoxia model, and the reversal of muscularisation is partial. exposure: Sildenafil 25 or 75 milligrams per kilogram per day started before hypoxia, or started after 14 days of established pulmonary hypertension evidence_span: {"source_cache": "artifacts/sildenafil-research/12796132.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "61d9020b6275a7c57fcee753c74b06c334ad034286eeaccdcbdf12e49b472122", "start_char": 0, "end_char": 1616, "text_sha256": "61d9020b6275a7c57fcee753c74b06c334ad034286eeaccdcbdf12e49b472122"} [sil-p12796132] Phosphodiesterase type 5 as a target for the treatment of hypoxia-induced pulmonary hypertension. (2003). https://pubmed.ncbi.nlm.nih.gov/12796132/ DOI: 10.1161/01.cir.0000074226.20466.b1
Complete structured claim and evidence
In ten patients with pulmonary hypertension either primary or related to previous left-to-right shunts, thromboembolism or interstitial lung disease and poorly controlled on conventional therapy, sildenafil 25 milligrams eight hourly for two weeks was associated compared with placebo with improved exercise tolerance on the six-minute walk test at 266.67 against 170 metres, a decrease in modified Borg dyspnea score from 5.11 to 3.56, a decrease in Doppler-estimated pulmonary artery systolic pressure from 75.33 to 55.33 millimetres of mercury, and improvement in New York Heart Association class in two patients, with no significant changes in heart rate or blood pressure.
Sildenafil → Six-minute walk distance source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/sildenafil-research/12760589.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "bca7bee4050068cd35e6f9f10a8de3c3a4505b4682eef9b8f91126ac1dbf38e5", "start_char": 0, "end_char": 2507, "text_sha256": "bca7bee4050068cd35e6f9f10a8de3c3a4505b4682eef9b8f91126ac1dbf38e5"}
experimental_model
Randomised double-blind placebo-controlled crossover trial in ten consecutive patients poorly controlled on conventional therapy
exposure
Sildenafil 25 milligrams every eight hours or matching placebo for two weeks each with a two-week run-in between
limitations
Ten patients of mixed aetiology, with pulmonary artery pressure estimated by echo Doppler rather than catheter, and a two-week exposure.
nutrient_topic
Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. · Sildenafil
organism
Human
plain_language
Two weeks of tablets let these patients walk nearly a hundred metres further and dropped the pressure in the lung.
primary_references
[sil-p12760589] The efficacy and tolerability of sildenafil in patients with moderate-to-severe pulmonary hypertension. (2003). https://pubmed.ncbi.nlm.nih.gov/12760589/
tissue_or_cell_type
Pulmonary circulation
Sildenafil: the enzyme it occupies instead of the substrate, why it cannot start a signal it can only preserve, the organic nitrate interaction that follows from that, the homologous retinal enzyme ten-fold away, and the pulmonary circulation where the same mechanism became a second indication (2026-09-22) · lines 574–585
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Randomised double-blind placebo-controlled crossover trial in ten consecutive patients poorly controlled on conventional therapy · source_derived_draft · unverified_draft
### sil-improves-walking-and-pressure In ten patients with pulmonary hypertension either primary or related to previous left-to-right shunts, thromboembolism or interstitial lung disease and poorly controlled on conventional therapy, sildenafil 25 milligrams eight hourly for two weeks was associated compared with placebo with improved exercise tolerance on the six-minute walk test at 266.67 against 170 metres, a decrease in modified Borg dyspnea score from 5.11 to 3.56, a decrease in Doppler-estimated pulmonary artery systolic pressure from 75.33 to 55.33 millimetres of mercury, and improvement in New York Heart Association class in two patients, with no significant changes in heart rate or blood pressure. Condition category: normal nutrient_topic: Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. plain_language: Two weeks of tablets let these patients walk nearly a hundred metres further and dropped the pressure in the lung. organism: Human tissue_or_cell_type: Pulmonary circulation experimental_model: Randomised double-blind placebo-controlled crossover trial in ten consecutive patients poorly controlled on conventional therapy limitations: Ten patients of mixed aetiology, with pulmonary artery pressure estimated by echo Doppler rather than catheter, and a two-week exposure. exposure: Sildenafil 25 milligrams every eight hours or matching placebo for two weeks each with a two-week run-in between evidence_span: {"source_cache": "artifacts/sildenafil-research/12760589.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "bca7bee4050068cd35e6f9f10a8de3c3a4505b4682eef9b8f91126ac1dbf38e5", "start_char": 0, "end_char": 2507, "text_sha256": "bca7bee4050068cd35e6f9f10a8de3c3a4505b4682eef9b8f91126ac1dbf38e5"} [sil-p12760589] The efficacy and tolerability of sildenafil in patients with moderate-to-severe pulmonary hypertension. (2003). https://pubmed.ncbi.nlm.nih.gov/12760589/
Complete structured claim and evidence
At low altitude under 10 percent inspired oxygen sildenafil 50 milligrams significantly increased arterial oxygen saturation during exercise, reduced systolic pulmonary artery pressure at rest and during exercise, and increased maximum workload from 130.6 to 172.5 watts and maximum cardiac output, while at Mount Everest base camp it had no effect on arterial oxygen saturation but still reduced systolic pulmonary artery pressure at rest and during exercise and increased maximum workload and cardiac output, exacerbating existing headache in two participants.
Sildenafil → Maximum workload on cycle ergometry source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/sildenafil-research/15289213.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "9767ed0c1022cee4fb74a2caef80b8ac9afd40077da8b6d1651fe0e631fde136", "start_char": 0, "end_char": 2481, "text_sha256": "9767ed0c1022cee4fb74a2caef80b8ac9afd40077da8b6d1651fe0e631fde136"}
experimental_model
Randomised double-blind placebo-controlled crossover study in fourteen mountaineers at low altitude under hypoxic gas and at Mount Everest base camp
exposure
Oral sildenafil 50 milligrams, with systolic pulmonary artery pressure, cardiac output and arterial oxygen saturation at rest and at maximum exercise
limitations
A crossover design carried out in two settings including genuine altitude. Fourteen participants, and the study did not examine normoxic exercise tolerance.
nutrient_topic
Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. · Sildenafil
organism
Human
plain_language
By lowering the pressure the lung raises against low oxygen, it let people work substantially harder.
primary_references
[sil-p15289213] Sildenafil increased exercise capacity during hypoxia at low altitudes and at Mount Everest base camp: a randomized, double-blind, placebo-controlled crossover trial. (2004). https://pubmed.ncbi.nlm.nih.gov/15289213/ DOI: 10.7326/0003-4819-141-3-200408030-00005
tissue_or_cell_type
Pulmonary circulation and exercise capacity
Sildenafil: the enzyme it occupies instead of the substrate, why it cannot start a signal it can only preserve, the organic nitrate interaction that follows from that, the homologous retinal enzyme ten-fold away, and the pulmonary circulation where the same mechanism became a second indication (2026-09-22) · lines 587–598
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Randomised double-blind placebo-controlled crossover study in fourteen mountaineers at low altitude under hypoxic gas and at Mount Everest base camp · source_derived_draft · unverified_draft
### sil-raises-exercise-capacity-in-hypoxia At low altitude under 10 percent inspired oxygen sildenafil 50 milligrams significantly increased arterial oxygen saturation during exercise, reduced systolic pulmonary artery pressure at rest and during exercise, and increased maximum workload from 130.6 to 172.5 watts and maximum cardiac output, while at Mount Everest base camp it had no effect on arterial oxygen saturation but still reduced systolic pulmonary artery pressure at rest and during exercise and increased maximum workload and cardiac output, exacerbating existing headache in two participants. Condition category: normal nutrient_topic: Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. plain_language: By lowering the pressure the lung raises against low oxygen, it let people work substantially harder. organism: Human tissue_or_cell_type: Pulmonary circulation and exercise capacity experimental_model: Randomised double-blind placebo-controlled crossover study in fourteen mountaineers at low altitude under hypoxic gas and at Mount Everest base camp limitations: A crossover design carried out in two settings including genuine altitude. Fourteen participants, and the study did not examine normoxic exercise tolerance. exposure: Oral sildenafil 50 milligrams, with systolic pulmonary artery pressure, cardiac output and arterial oxygen saturation at rest and at maximum exercise evidence_span: {"source_cache": "artifacts/sildenafil-research/15289213.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "9767ed0c1022cee4fb74a2caef80b8ac9afd40077da8b6d1651fe0e631fde136", "start_char": 0, "end_char": 2481, "text_sha256": "9767ed0c1022cee4fb74a2caef80b8ac9afd40077da8b6d1651fe0e631fde136"} [sil-p15289213] Sildenafil increased exercise capacity during hypoxia at low altitudes and at Mount Everest base camp: a randomized, double-blind, placebo-controlled crossover trial. (2004). https://pubmed.ncbi.nlm.nih.gov/15289213/ DOI: 10.7326/0003-4819-141-3-200408030-00005
Complete structured claim and evidence
Cyclic GMP and its primary signalling kinase protein kinase G play a role in counterbalancing stress remodelling in the heart, growing evidence supports a positive impact on a variety of cardiac disease conditions from suppression of cyclic GMP hydrolysis which is regulated by phosphodiesterase family members of which cyclic-GMP-selective PDE5 has been best studied, and inhibitors such as sildenafil and tadalafil ameliorate cardiac pressure and volume overload, ischaemic injury and cardiotoxicity, with clinical trials begun to explore dilated cardiomyopathy and heart failure with preserved ejection fraction.
Phosphodiesterase 5 family → Cyclic guanosine monophosphate source_derived_draftungraded
Experimental context and source evidence
evidence_span
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experimental_model
Review of cyclic GMP and protein kinase G signalling in cardiac stress remodelling
exposure
Phosphodiesterase type 5 inhibition across models of pressure and volume overload, ischaemic injury and cardiotoxicity
limitations
A review summarising preclinical work and stating the clinical trials as ongoing. It reports the expectation that the trial in the next record went on to test.
nutrient_topic
Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. · Sildenafil
organism
Animal and human
plain_language
In animal hearts under strain, blocking this enzyme helped, and that is what the trials set out to confirm.
primary_references
[sil-p22798047] Cardiac role of cyclic-GMP hydrolyzing phosphodiesterase type 5: from experimental models to clinical trials. (2012). https://pubmed.ncbi.nlm.nih.gov/22798047/ DOI: 10.1007/s11897-012-0101-0
tissue_or_cell_type
Myocardium
Sildenafil: the enzyme it occupies instead of the substrate, why it cannot start a signal it can only preserve, the organic nitrate interaction that follows from that, the homologous retinal enzyme ten-fold away, and the pulmonary circulation where the same mechanism became a second indication (2026-09-22) · lines 600–611
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Review of cyclic GMP and protein kinase G signalling in cardiac stress remodelling · source_derived_draft · unverified_draft
### sil-preclinical-cardiac-promise Cyclic GMP and its primary signalling kinase protein kinase G play a role in counterbalancing stress remodelling in the heart, growing evidence supports a positive impact on a variety of cardiac disease conditions from suppression of cyclic GMP hydrolysis which is regulated by phosphodiesterase family members of which cyclic-GMP-selective PDE5 has been best studied, and inhibitors such as sildenafil and tadalafil ameliorate cardiac pressure and volume overload, ischaemic injury and cardiotoxicity, with clinical trials begun to explore dilated cardiomyopathy and heart failure with preserved ejection fraction. Condition category: normal nutrient_topic: Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. plain_language: In animal hearts under strain, blocking this enzyme helped, and that is what the trials set out to confirm. organism: Animal and human tissue_or_cell_type: Myocardium experimental_model: Review of cyclic GMP and protein kinase G signalling in cardiac stress remodelling limitations: A review summarising preclinical work and stating the clinical trials as ongoing. It reports the expectation that the trial in the next record went on to test. exposure: Phosphodiesterase type 5 inhibition across models of pressure and volume overload, ischaemic injury and cardiotoxicity evidence_span: {"source_cache": "artifacts/sildenafil-research/22798047.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "5456b43dcdb907d5a82ca9999cc94cb6c584589d0b454e1cdbf44fb3ee40941f", "start_char": 0, "end_char": 799, "text_sha256": "5456b43dcdb907d5a82ca9999cc94cb6c584589d0b454e1cdbf44fb3ee40941f"} [sil-p22798047] Cardiac role of cyclic-GMP hydrolyzing phosphodiesterase type 5: from experimental models to clinical trials. (2012). https://pubmed.ncbi.nlm.nih.gov/22798047/ DOI: 10.1007/s11897-012-0101-0
Complete structured claim and evidence
In cardiac myocytes cyclic GMP is produced by soluble and particulate guanylyl cyclases, the former stimulated by nitric oxide and the latter by natriuretic peptides, and is hydrolyzed to inactive 5-GMP by cyclic GMP phosphodiesterases, cyclic GMP and protein kinase G modulate cardiac contractility, hypertrophy and remodeling and exert cardioprotection, recent studies have revealed that cyclic GMP degradation controlled by phosphodiesterases plays a critical role in the physiological action of cyclic GMP, and several clinical trials are ongoing including a large multicenter trial led by the NIH evaluating sildenafil efficacy in heart failure with preserved ejection fraction.
Membrane-bound particulate guanylate cyclase and other non-nitric-oxide sources of cyclic GMP → Cyclic guanosine monophosphate source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/sildenafil-research/22785374.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "14560978d3bfa37c665443c993d21b9c4a0e287c6c8c45672ee35ed55f0c6094", "start_char": 0, "end_char": 1262, "text_sha256": "14560978d3bfa37c665443c993d21b9c4a0e287c6c8c45672ee35ed55f0c6094"}
experimental_model
Review of cyclic GMP and protein kinase G signal regulation in the cardiac myocyte
exposure
Sources and degradation of cyclic GMP in the myocyte, and phosphodiesterase type 5 inhibition across cardiac pathologies
limitations
A review written while the definitive trial was still running, and it names that trial as the test of its own thesis.
nutrient_topic
Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. · Sildenafil
organism
Animal and human
plain_language
The messenger has a second source that answers to natriuretic peptides rather than nitric oxide.
primary_references
[sil-p22785374] Cyclic GMP-dependent signaling in cardiac myocytes. (2012). https://pubmed.ncbi.nlm.nih.gov/22785374/ DOI: 10.1253/circj.cj-12-0664
tissue_or_cell_type
Cardiac myocyte
Sildenafil: the enzyme it occupies instead of the substrate, why it cannot start a signal it can only preserve, the organic nitrate interaction that follows from that, the homologous retinal enzyme ten-fold away, and the pulmonary circulation where the same mechanism became a second indication (2026-09-22) · lines 613–624
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Review of cyclic GMP and protein kinase G signal regulation in the cardiac myocyte · source_derived_draft · unverified_draft
### sil-two-sources-of-the-messenger In cardiac myocytes cyclic GMP is produced by soluble and particulate guanylyl cyclases, the former stimulated by nitric oxide and the latter by natriuretic peptides, and is hydrolyzed to inactive 5-GMP by cyclic GMP phosphodiesterases, cyclic GMP and protein kinase G modulate cardiac contractility, hypertrophy and remodeling and exert cardioprotection, recent studies have revealed that cyclic GMP degradation controlled by phosphodiesterases plays a critical role in the physiological action of cyclic GMP, and several clinical trials are ongoing including a large multicenter trial led by the NIH evaluating sildenafil efficacy in heart failure with preserved ejection fraction. Condition category: normal nutrient_topic: Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. plain_language: The messenger has a second source that answers to natriuretic peptides rather than nitric oxide. organism: Animal and human tissue_or_cell_type: Cardiac myocyte experimental_model: Review of cyclic GMP and protein kinase G signal regulation in the cardiac myocyte limitations: A review written while the definitive trial was still running, and it names that trial as the test of its own thesis. exposure: Sources and degradation of cyclic GMP in the myocyte, and phosphodiesterase type 5 inhibition across cardiac pathologies evidence_span: {"source_cache": "artifacts/sildenafil-research/22785374.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "14560978d3bfa37c665443c993d21b9c4a0e287c6c8c45672ee35ed55f0c6094", "start_char": 0, "end_char": 1262, "text_sha256": "14560978d3bfa37c665443c993d21b9c4a0e287c6c8c45672ee35ed55f0c6094"} [sil-p22785374] Cyclic GMP-dependent signaling in cardiac myocytes. (2012). https://pubmed.ncbi.nlm.nih.gov/22785374/ DOI: 10.1253/circj.cj-12-0664
Complete structured claim and evidence
Among 216 patients with heart failure and preserved ejection fraction randomised to sildenafil or placebo for 24 weeks, median changes in peak oxygen consumption were not significantly different with a mean between-group difference of 0.01 millilitres per kilogram per minute, the mean clinical status rank score was not significantly different at 95.8 for placebo and 94.2 for sildenafil, and changes in six-minute walk distance were not significantly different, with serious adverse events in 16% of placebo and 22% of sildenafil patients.
Sildenafil → Peak oxygen consumption source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/sildenafil-research/23478662.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "563c3c4bab090bd15f4627c45776c1b7cba040d7532cd85102d059753df3f8d1", "start_char": 0, "end_char": 3109, "text_sha256": "563c3c4bab090bd15f4627c45776c1b7cba040d7532cd85102d059753df3f8d1"}
experimental_model
Multicentre double-blind placebo-controlled randomised trial in 216 outpatients with heart failure and preserved ejection fraction
exposure
Sildenafil 20 milligrams three times daily for 12 weeks then 60 milligrams three times daily for 12 weeks
limitations
An adequately powered randomised trial with an objective primary endpoint, reported as fully negative. Its participants had elevated filling pressures and pulmonary artery systolic pressure of 41 millimetres of mercury, so the target population was appropriate.
nutrient_topic
Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. · Sildenafil
organism
Human
plain_language
In a proper trial in the condition the animal work pointed at, the drug did nothing at all.
primary_references
[sil-p23478662] Effect of phosphodiesterase-5 inhibition on exercise capacity and clinical status in heart failure with preserved ejection fraction: a randomized clinical trial. (2013). https://pubmed.ncbi.nlm.nih.gov/23478662/ DOI: 10.1001/jama.2013.2024
tissue_or_cell_type
Cardiopulmonary exercise capacity
Sildenafil: the enzyme it occupies instead of the substrate, why it cannot start a signal it can only preserve, the organic nitrate interaction that follows from that, the homologous retinal enzyme ten-fold away, and the pulmonary circulation where the same mechanism became a second indication (2026-09-22) · lines 626–637
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Multicentre double-blind placebo-controlled randomised trial in 216 outpatients with heart failure and preserved ejection fraction · source_derived_draft · unverified_draft
### sil-no-benefit-in-hfpef Among 216 patients with heart failure and preserved ejection fraction randomised to sildenafil or placebo for 24 weeks, median changes in peak oxygen consumption were not significantly different with a mean between-group difference of 0.01 millilitres per kilogram per minute, the mean clinical status rank score was not significantly different at 95.8 for placebo and 94.2 for sildenafil, and changes in six-minute walk distance were not significantly different, with serious adverse events in 16% of placebo and 22% of sildenafil patients. Condition category: normal nutrient_topic: Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. plain_language: In a proper trial in the condition the animal work pointed at, the drug did nothing at all. organism: Human tissue_or_cell_type: Cardiopulmonary exercise capacity experimental_model: Multicentre double-blind placebo-controlled randomised trial in 216 outpatients with heart failure and preserved ejection fraction limitations: An adequately powered randomised trial with an objective primary endpoint, reported as fully negative. Its participants had elevated filling pressures and pulmonary artery systolic pressure of 41 millimetres of mercury, so the target population was appropriate. exposure: Sildenafil 20 milligrams three times daily for 12 weeks then 60 milligrams three times daily for 12 weeks evidence_span: {"source_cache": "artifacts/sildenafil-research/23478662.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "563c3c4bab090bd15f4627c45776c1b7cba040d7532cd85102d059753df3f8d1", "start_char": 0, "end_char": 3109, "text_sha256": "563c3c4bab090bd15f4627c45776c1b7cba040d7532cd85102d059753df3f8d1"} [sil-p23478662] Effect of phosphodiesterase-5 inhibition on exercise capacity and clinical status in heart failure with preserved ejection fraction: a randomized clinical trial. (2013). https://pubmed.ncbi.nlm.nih.gov/23478662/ DOI: 10.1001/jama.2013.2024
Complete structured claim and evidence

Availability and dependencies

Each situation shows the normal role first, then what the sources report under a specific condition. A shortfall in the diet, a fault in the machinery, and a low blood reading are kept separate because they are not the same thing.

When there is no nitric oxide signal to preserve

Condition: biomarker_context · Absence of nitric oxide drive, as in unstimulated isolated tissue.

Normal role: Sildenafil prevents the degradation of cyclic GMP that nitric oxide has caused guanylate cyclase to produce.

Recorded consequence: The drug has no functional effect of its own on isolated corpus cavernosum, and in the anaesthetised dog it does not raise intracavernosal pressure until the pelvic nerve is stimulated; it potentiates a response rather than initiating one.

Scope: Isolated human and rabbit tissue and anaesthetised dogs

When an organic nitrate is given as well

Condition: biomarker_context · Coadministration of any organic nitrate or nitric oxide donor, regularly or intermittently.

Normal role: Nitrates and sildenafil both raise cyclic GMP in the systemic circulation, but at different points: a nitrate supplies nitric oxide so that guanylate cyclase makes more, while sildenafil prevents what is made from being destroyed.

Recorded consequence: The hypotensive effect is potentiated rather than merely added: a sublingual nitrate tablet produced a fourfold greater fall in systolic pressure, and tolerance of an intravenous nitrate infusion was significantly reduced. The combination is contraindicated.

Scope: Double-blind placebo-controlled crossover studies in healthy men

When the enzyme that clears the drug is inhibited

Condition: machinery_impairment · Coadministration of a potent CYP3A4 inhibitor such as ketoconazole or ritonavir, or renal or hepatic impairment.

Normal role: Sildenafil is cleared mainly by CYP3A4-mediated piperazine N-demethylation, with CYP2C9 contributing.

Recorded consequence: Systemic exposure rises, and because the hypotensive effect of this drug depends on plasma concentration, the cardiovascular consequences rise with it.

Scope: Human liver microsomes and expressed cytochromes

When endothelial nitric oxide synthase is absent

Condition: machinery_impairment · Genetic deletion of endothelial nitric oxide synthase in mice.

Normal role: The drug preserves cyclic GMP that nitric oxide has caused guanylate cyclase to make, so removing the main endothelial source of nitric oxide would be expected to remove its effect.

Recorded consequence: Sildenafil still markedly blunts acute hypoxic pulmonary vasoconstriction and still attenuates the rise in right ventricular systolic pressure, though without a significant effect on right ventricular hypertrophy or vascular remodelling, indicating that other biochemical sources of cyclic GMP contribute.

Scope: Isolated perfused lung and chronic hypoxia in knockout mice

The sources

Every document behind this chapter is preserved word for word. Open one to read it in full with its recorded conflicts marked in place.

Sildenafil: the enzyme it occupies instead of the substrate, why it cannot start a signal it can only preserve, the organic nitrate interaction that follows from that, the homologous retinal enzyme ten-fold away, and the pulmonary circulation where the same mechanism became a second indication (2026-09-22)AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · unverified_draftRead preserved source

Recorded disagreements

Where two sources say different things, both are kept and the difference is explained. You can discuss a disagreement or propose a mechanism that might account for it.

Does inhibiting this enzyme help the failing heart?Preclinical work across models of pressure and volume overload, ischaemic injury and cardiotoxicity supported a benefit from suppressing cyclic GMP hydrolysis in the heart, and reviews written while trials were running described the rationale as growing evidence. A multicentre randomised trial of 216 patients with heart failure and preserved ejection fraction, dosed for 24 weeks and escalated to 60 milligrams three times daily, found no difference whatever in peak oxygen consumption, clinical status or six-minute walk distance. A third record in this collection offers a possible reason that was available before the trial: immunochemical mapping of human tissue found the major phosphodiesterase of the human cardiac ventricle to be the calcium and calmodulin-dependent PDE1, with no detectable PDE5, and found no functional effect of sildenafil on isolated cardiac trabeculae. If the target is not expressed in the human myocardium, a drug against it would not be expected to remodel it, whatever the animal models show. The absence of a target is antibody-based and therefore weaker evidence than its presence would be, and the trial does not exclude benefit in other cardiac conditions. The trial was also contested in print: a letter and an authors' reply followed in the same journal, neither of which carries an abstract through any accessed endpoint, so the exchange is recorded here as existing and unread.Read the recorded disagreement
Does sildenafil need nitric oxide to do anything?The founding pharmacology states the principle plainly: with no nitric oxide drive the drug had no functional effect on isolated human or rabbit corpus cavernosum, and in the anaesthetised dog it did not raise intracavernosal pressure at all until the pelvic nerve was stimulated. The same pattern holds in platelets, where inhibiting the enzyme alone does not affect aggregation but does in the presence of a nitric oxide donor. Against that, two organ bath studies of human penile and conduit vessels found concentration-dependent relaxation by sildenafil alone that was unaffected by nitric oxide synthase inhibition, and in isolated perfused lung the drug blunted hypoxic pulmonary vasoconstriction in mice lacking endothelial nitric oxide synthase, whose authors concluded that other biochemical sources of cyclic GMP also contribute. The records are reconcilable if the requirement is read correctly: what the drug needs is an ongoing supply of cyclic GMP, not specifically endothelial nitric oxide, and vessels with basal tone or a particulate guanylate cyclase input have such a supply where quiescent cavernosal tissue does not. The organ bath work also used concentrations reaching the micromolar range, far above those that inhibit the enzyme, and in the intact human coronary circulation the drug produced no significant change in resting coronary blood flow, which is what a direct relaxant acting independently of upstream drive would have been expected to change. That reading is a synthesis rather than a measurement, and no record here tests it directly.Read the recorded disagreement
Does sildenafil raise cyclic GMP, or cyclic AMP?The mechanism requires that inhibiting a cyclic-GMP-specific phosphodiesterase raises cyclic GMP and leaves cyclic AMP alone, and one study reports exactly that: the drug selectively increased cyclic GMP in coronary vascular smooth muscle with no change in cyclic AMP, and enhanced nitroprusside-driven cyclic GMP accumulation in rabbit corpus cavernosum without affecting cyclic AMP. A study of isolated human cavernous and cardiac tissue found the opposite pattern, with only a minor effect on cyclic GMP across 0.01 to 1 micromolar and a significant rise in cyclic AMP in both tissues, almost equivalent to milrinone in the cardiac samples, and proposed cross-talk between the pathways. The designs differ in an important way: the studies reporting a cyclic GMP rise supplied nitric oxide drive with a donor, and a phosphodiesterase inhibitor cannot raise a messenger that is not being made, whereas the dissenting study measured accumulation without such drive. Whether the cyclic AMP rise is a genuine second action or an artefact of tissue and conditions is not resolved here, and it is recorded because it was offered as an explanation for cardiovascular effects. One further fact belongs on this disagreement rather than inside either record: the dissenting paper drew a published letter in the same journal from Corbin, Francis and Osterloh, and the first two are the enzymologists whose work on the phosphorylation and allosteric binding of this enzyme is cited elsewhere in this chapter. That letter carries no abstract through any accessed endpoint, so its argument has not been read and is recorded as existing rather than as a refutation.Read the recorded disagreement

Open questions in this collection

Questions the curators could not answer from the sources in front of them, kept here with the reason each one is still open. These are gaps in this collection, not findings or proof that no one has studied them.

Why this drug lowers systemic blood pressure by about 10 over 7 millimetres of mercury if its target is absent from the myocardium and the effect requires upstream nitric oxide.The enzyme is present in saphenous vein and mesenteric artery and absent from cardiac ventricle, the fall is not dose related, and two organ bath studies found direct relaxation of human vessels that survived nitric oxide synthase inhibition. No record here reconciles the magnitude of the systemic effect with the tissue distribution.
Whether the roughly tenfold selectivity over retinal PDE6 is enough at the top of the therapeutic range.Retinal effects in the dog appeared only at plasma concentrations about thirty-fold above those active on intracavernosal pressure, colour vision defects are dose related in people, and long-term electroretinographic studies had not been performed at the time of the ocular reviews recorded here.
What supplies the cyclic GMP when endothelial nitric oxide synthase is deleted.Sildenafil still blunted hypoxic pulmonary vasoconstriction and still attenuated right ventricular systolic pressure in knockout mice, and those authors attributed this to other biochemical sources of cyclic GMP without identifying them. A review in this collection names the particulate guanylyl cyclase answering to natriuretic peptides as the second source in the cardiac myocyte, but no record here tests whether that is what sustains the drug effect in the knockout lung.
Whether the rise in cyclic AMP reported in isolated human tissue is a real second action of the drug.One study found only a minor effect on cyclic GMP across 0.01 to 1 micromolar with a significant rise in cyclic AMP in both cavernous and cardiac tissue, almost equivalent to milrinone in the cardiac samples, while other records report selective cyclic GMP elevation with no change in cyclic AMP. The studies differ in whether nitric oxide drive was supplied.
Whether the structural effects in the pulmonary circulation depend on the same pathway as the haemodynamic ones.In endothelial nitric oxide synthase knockout mice the drug attenuated the rise in right ventricular systolic pressure but had no significant effect on right ventricular hypertrophy or vascular remodelling, so the pressure effect and the remodelling effect came apart when the pathway was removed.

Chapters are assembled from supplied drafts and curated literature summaries. Statements remain unverified against the primary studies, and the ledger is not medical advice.

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