Zaprinast

Where it participates (unsigned role)

1. 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

2. 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

3. 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

4. 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