Sildenafil

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

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

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

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

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

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

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

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

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/

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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/

duration

Not applicable

evidence_access

Primary PubMed abstract and indexed metadata reviewed. Full-text method details not stated here remain unresolved.

experimental_model

Human PDE5 catalytic domain

exposure

Each of the three drug molecules complexed with the enzyme

limitations

The catalytic domain alone was crystallised, not the full-length regulated enzyme, so the structures do not describe the allosteric cGMP-binding GAF domains.

organism

Human PDE5 catalytic domain

plain_language

Three-dimensional structures of the catalytic domain of human PDE5, residues 537 to 860, were determined in complex with sildenafil, tadalafil and vardenafil.

primary_references

Structure of the catalytic domain of human phosphodiesterase 5 with bound drug molecules. (2003). https://pubmed.ncbi.nlm.nih.gov/12955149/ DOI: 10.1038/nature01914

route

Structural

tissue

Inhibitor binding at the catalytic site

Tadalafil: PDE5 occupancy, the cGMP route and three measured endpoints (2026-09-22) · lines 35–44

Original AI-assisted curation of seven primary studies resolved by PubMed title search, with every abstract read and all DOIs cross-checked against live PubMed metadata. Two references carry an unresolvable erratum and are recorded as corrected. Study-specific doses, effect sizes and limitations retained. Not publisher full text. · supports · · source_derived_draft · unverified_draft

## pde5-binding-site-resolved-with-tadalafil Three-dimensional structures of the catalytic domain of human PDE5, residues 537 to 860, were determined in complex with sildenafil, tadalafil and vardenafil. Model/species: Human PDE5 catalytic domain Tissue/system: Inhibitor binding at the catalytic site Exposure: Each of the three drug molecules complexed with the enzyme Route: Structural Duration: Not applicable Limits: The catalytic domain alone was crystallised, not the full-length regulated enzyme, so the structures do not describe the allosteric cGMP-binding GAF domains. Primary reference: Structure of the catalytic domain of human phosphodiesterase 5 with bound drug molecules. (2003). https://pubmed.ncbi.nlm.nih.gov/12955149/ DOI: 10.1038/nature01914 Access: Primary PubMed abstract and indexed metadata reviewed. Full-text method details not stated here remain unresolved.

duration

Not applicable

evidence_access

Primary PubMed abstract and indexed metadata reviewed. Full-text method details not stated here remain unresolved.

experimental_model

Isolated phosphodiesterase enzyme assays

exposure

Tadalafil compared with sildenafil

limitations

A ratio measured in enzyme assays; PDE6 is the retinal phototransduction phosphodiesterase, and this comparison does not by itself establish a difference in visual effects in people.

organism

Isolated phosphodiesterase enzyme assays

plain_language

Tadalafil showed 85-fold greater selectivity against PDE6 than sildenafil.

primary_references

The discovery of tadalafil: a novel and highly selective PDE5 inhibitor. 2. (2003). https://pubmed.ncbi.nlm.nih.gov/14521415/ DOI: 10.1021/jm0300577

route

In vitro

tissue

Selectivity ratio between PDE5 and PDE6

Tadalafil: PDE5 occupancy, the cGMP route and three measured endpoints (2026-09-22) · lines 24–33

Original AI-assisted curation of seven primary studies resolved by PubMed title search, with every abstract read and all DOIs cross-checked against live PubMed metadata. Two references carry an unresolvable erratum and are recorded as corrected. Study-specific doses, effect sizes and limitations retained. Not publisher full text. · supports · · source_derived_draft · unverified_draft

## tadalafil-pde6-selectivity-versus-sildenafil Tadalafil showed 85-fold greater selectivity against PDE6 than sildenafil. Model/species: Isolated phosphodiesterase enzyme assays Tissue/system: Selectivity ratio between PDE5 and PDE6 Exposure: Tadalafil compared with sildenafil Route: In vitro Duration: Not applicable Limits: A ratio measured in enzyme assays; PDE6 is the retinal phototransduction phosphodiesterase, and this comparison does not by itself establish a difference in visual effects in people. Primary reference: The discovery of tadalafil: a novel and highly selective PDE5 inhibitor. 2. (2003). https://pubmed.ncbi.nlm.nih.gov/14521415/ DOI: 10.1021/jm0300577 Access: Primary PubMed abstract and indexed metadata reviewed. Full-text method details not stated here remain unresolved.