The nitric oxide to soluble guanylate cyclase to cyclic GMP pathway

Where it participates (unsigned role)

1. Sildenafil is a potent competitive inhibitor of PDE5 with a half-maximal inhibitory concentration of 3.5 nanomolar, selective over PDE1 to PDE4 by 80 to 19,000-fold and over retinal PDE6 by 10-fold, it enhanced cyclic GMP accumulation driven with sodium nitroprusside in rabbit corpus cavernosum without affecting cyclic AMP, and in the absence of nitric oxide drive it had no functional effect on human and rabbit isolated corpus cavernosum but potently potentiated the relaxant effects of nitric oxide on these tissues.

   Sildenafil → Relaxation of vascular and trabecular smooth muscle source_derived_draftungraded
   Experimental context and source evidence

   availability_state

   biomarker_context Imported condition classification; unverified.

   evidence_span

   {"source_cache": "artifacts/sildenafil-research/10629850.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "af056c516b44e35eac7b0511ba3a8403ed84c347af6094ebc153f68c8ee7db92", "start_char": 0, "end_char": 2057, "text_sha256": "af056c516b44e35eac7b0511ba3a8403ed84c347af6094ebc153f68c8ee7db92"}

   experimental_model

   Enzyme selectivity panel with isolated tissue, anaesthetised dog haemodynamics and isolated retina

   exposure

   Sildenafil with and without nitric oxide drive, and against glyceryl trinitrate, sodium nitroprusside and milrinone

   limitations

   The single most complete pharmacological characterisation here, covering the target, the absence of effect without upstream drive, the nitrate potentiation, the absence of an inotropic effect, and the retinal effect in one series.

   nutrient_topic

   Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. · Sildenafil

   organism

   Human, rabbit and dog

   plain_language

   With no signal present the drug does nothing; its entire action is to keep an existing signal from being cleared.

   primary_references

   [sil-p10629850] The pharmacology of sildenafil, a novel and selective inhibitor of phosphodiesterase (PDE) type 5. (1999). https://pubmed.ncbi.nlm.nih.gov/10629850/ DOI: 10.1254/fpj.114.supplement_22

   tissue_or_cell_type

   Corpus cavernosum, aorta, cardiac trabeculae and retina

   trigger_kind

   biomarker_context Imported condition classification; unverified.

   Sildenafil: the enzyme it occupies instead of the substrate, why it cannot start a signal it can only preserve, the organic nitrate interaction that follows from that, the homologous retinal enzyme ten-fold away, and the pulmonary circulation where the same mechanism became a second indication (2026-09-22) · lines 262–273

   AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Enzyme selectivity panel with isolated tissue, anaesthetised dog haemodynamics and isolated retina · source_derived_draft · unverified_draft

   ### sil-no-effect-without-nitric-oxide Sildenafil is a potent competitive inhibitor of PDE5 with a half-maximal inhibitory concentration of 3.5 nanomolar, selective over PDE1 to PDE4 by 80 to 19,000-fold and over retinal PDE6 by 10-fold, it enhanced cyclic GMP accumulation driven with sodium nitroprusside in rabbit corpus cavernosum without affecting cyclic AMP, and in the absence of nitric oxide drive it had no functional effect on human and rabbit isolated corpus cavernosum but potently potentiated the relaxant effects of nitric oxide on these tissues. Condition category: biomarker_context nutrient_topic: Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. plain_language: With no signal present the drug does nothing; its entire action is to keep an existing signal from being cleared. organism: Human, rabbit and dog tissue_or_cell_type: Corpus cavernosum, aorta, cardiac trabeculae and retina experimental_model: Enzyme selectivity panel with isolated tissue, anaesthetised dog haemodynamics and isolated retina limitations: The single most complete pharmacological characterisation here, covering the target, the absence of effect without upstream drive, the nitrate potentiation, the absence of an inotropic effect, and the retinal effect in one series. exposure: Sildenafil with and without nitric oxide drive, and against glyceryl trinitrate, sodium nitroprusside and milrinone evidence_span: {"source_cache": "artifacts/sildenafil-research/10629850.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "af056c516b44e35eac7b0511ba3a8403ed84c347af6094ebc153f68c8ee7db92", "start_char": 0, "end_char": 2057, "text_sha256": "af056c516b44e35eac7b0511ba3a8403ed84c347af6094ebc153f68c8ee7db92"} [sil-p10629850] The pharmacology of sildenafil, a novel and selective inhibitor of phosphodiesterase (PDE) type 5. (1999). https://pubmed.ncbi.nlm.nih.gov/10629850/ DOI: 10.1254/fpj.114.supplement_22

   Complete structured claim and evidence

2. Chronic hypoxia decreased RhoA messenger RNA and protein expression in rat main pulmonary artery and abolished RhoA-mediated calcium sensitisation of contraction, accounting for the decreased responses to endothelin-1, noradrenaline and a thromboxane analogue, and treatment with sildenafil at 25 milligrams per kilogram daily throughout the exposure prevented the downregulation of RhoA, the reduction of contraction and the pulmonary artery remodelling, indicating a major role of the nitric oxide and cyclic GMP pathway in the altered RhoA signalling.

   Sildenafil → RhoA and Rho-kinase-mediated calcium sensitisation of contraction source_derived_draftungraded
   Experimental context and source evidence

   evidence_span

   {"source_cache": "artifacts/sildenafil-research/12946946.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "ce3f4a451c01082a280ebffc7e9661ec5667161f4974b39ba15c52fa940754f7", "start_char": 0, "end_char": 1768, "text_sha256": "ce3f4a451c01082a280ebffc7e9661ec5667161f4974b39ba15c52fa940754f7"}

   experimental_model

   Rat pulmonary artery contractility and RhoA expression after two weeks of chronic hypoxia

   exposure

   Sildenafil 25 milligrams per kilogram daily through two weeks of 10 percent oxygen, with real-time PCR and western blotting

   limitations

   Identifies a second arm of the mechanism beyond cyclic-GMP-mediated relaxation. A rat chronic hypoxia model, and the causal chain from cyclic GMP to RhoA expression is inferred rather than dissected.

   nutrient_topic

   Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. · Sildenafil

   organism

   Rat

   plain_language

   Beyond relaxing the vessel, the drug preserved the contractile machinery that chronic low oxygen otherwise degrades.

   primary_references

   [sil-p12946946] Sildenafil prevents change in RhoA expression induced by chronic hypoxia in rat pulmonary artery. (2003). https://pubmed.ncbi.nlm.nih.gov/12946946/ DOI: 10.1161/01.res.0000093220.90027.d9

   tissue_or_cell_type

   Pulmonary artery

   Sildenafil: the enzyme it occupies instead of the substrate, why it cannot start a signal it can only preserve, the organic nitrate interaction that follows from that, the homologous retinal enzyme ten-fold away, and the pulmonary circulation where the same mechanism became a second indication (2026-09-22) · lines 548–559

   AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Rat pulmonary artery contractility and RhoA expression after two weeks of chronic hypoxia · source_derived_draft · unverified_draft

   ### sil-prevents-rhoa-downregulation Chronic hypoxia decreased RhoA messenger RNA and protein expression in rat main pulmonary artery and abolished RhoA-mediated calcium sensitisation of contraction, accounting for the decreased responses to endothelin-1, noradrenaline and a thromboxane analogue, and treatment with sildenafil at 25 milligrams per kilogram daily throughout the exposure prevented the downregulation of RhoA, the reduction of contraction and the pulmonary artery remodelling, indicating a major role of the nitric oxide and cyclic GMP pathway in the altered RhoA signalling. Condition category: normal nutrient_topic: Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. plain_language: Beyond relaxing the vessel, the drug preserved the contractile machinery that chronic low oxygen otherwise degrades. organism: Rat tissue_or_cell_type: Pulmonary artery experimental_model: Rat pulmonary artery contractility and RhoA expression after two weeks of chronic hypoxia limitations: Identifies a second arm of the mechanism beyond cyclic-GMP-mediated relaxation. A rat chronic hypoxia model, and the causal chain from cyclic GMP to RhoA expression is inferred rather than dissected. exposure: Sildenafil 25 milligrams per kilogram daily through two weeks of 10 percent oxygen, with real-time PCR and western blotting evidence_span: {"source_cache": "artifacts/sildenafil-research/12946946.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "ce3f4a451c01082a280ebffc7e9661ec5667161f4974b39ba15c52fa940754f7", "start_char": 0, "end_char": 1768, "text_sha256": "ce3f4a451c01082a280ebffc7e9661ec5667161f4974b39ba15c52fa940754f7"} [sil-p12946946] Sildenafil prevents change in RhoA expression induced by chronic hypoxia in rat pulmonary artery. (2003). https://pubmed.ncbi.nlm.nih.gov/12946946/ DOI: 10.1161/01.res.0000093220.90027.d9

   Complete structured claim and evidence

3. Sildenafil alone can cause mean peak reductions in systolic and diastolic blood pressure of 10 and 7 millimetres of mercury that are not dose related while heart rate is unchanged, and sildenafil and nitrates both increase cyclic GMP levels in the systemic circulation but at different points along the nitric oxide to cyclic GMP pathway, so the combination is contraindicated because they synergistically potentiate vasodilation; retrospective analysis of concomitant antihypertensive medications did not indicate an increase in adverse events, and concurrent renal or hepatic impairment or CYP3A4 inhibitors could increase systemic exposure.

   Sildenafil → Cyclic guanosine monophosphate source_derived_draftungraded
   Experimental context and source evidence

   availability_state

   biomarker_context Imported condition classification; unverified.

   evidence_span

   {"source_cache": "artifacts/sildenafil-research/10078541.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "e65228d2afaad9ce38dccf42c7279ec6b562746aa27b121bf5e5782f36cbe593", "start_char": 0, "end_char": 2772, "text_sha256": "e65228d2afaad9ce38dccf42c7279ec6b562746aa27b121bf5e5782f36cbe593"}

   experimental_model

   Review of the cardiovascular profile from the clinical development programme and post-marketing surveillance

   exposure

   Sildenafil alone and with antihypertensive classes, across clinical trials and spontaneous reports

   limitations

   A manufacturer-authored review of the development programme rather than an independent analysis, and the post-marketing comparisons are retrospective.

   nutrient_topic

   Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. · Sildenafil

   organism

   Human

   plain_language

   Both act on the same pathway at different points, which is why together they multiply rather than add.

   primary_references

   [sil-p10078541] Overall cardiovascular profile of sildenafil citrate. (1999). https://pubmed.ncbi.nlm.nih.gov/10078541/ DOI: 10.1016/s0002-9149(99)00046-6

   tissue_or_cell_type

   Cardiovascular system

   trigger_kind

   biomarker_context Imported condition classification; unverified.

   Sildenafil: the enzyme it occupies instead of the substrate, why it cannot start a signal it can only preserve, the organic nitrate interaction that follows from that, the homologous retinal enzyme ten-fold away, and the pulmonary circulation where the same mechanism became a second indication (2026-09-22) · lines 431–442

   AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Review of the cardiovascular profile from the clinical development programme and post-marketing surveillance · source_derived_draft · unverified_draft

   ### sil-two-points-on-one-pathway Sildenafil alone can cause mean peak reductions in systolic and diastolic blood pressure of 10 and 7 millimetres of mercury that are not dose related while heart rate is unchanged, and sildenafil and nitrates both increase cyclic GMP levels in the systemic circulation but at different points along the nitric oxide to cyclic GMP pathway, so the combination is contraindicated because they synergistically potentiate vasodilation; retrospective analysis of concomitant antihypertensive medications did not indicate an increase in adverse events, and concurrent renal or hepatic impairment or CYP3A4 inhibitors could increase systemic exposure. Condition category: biomarker_context nutrient_topic: Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. plain_language: Both act on the same pathway at different points, which is why together they multiply rather than add. organism: Human tissue_or_cell_type: Cardiovascular system experimental_model: Review of the cardiovascular profile from the clinical development programme and post-marketing surveillance limitations: A manufacturer-authored review of the development programme rather than an independent analysis, and the post-marketing comparisons are retrospective. exposure: Sildenafil alone and with antihypertensive classes, across clinical trials and spontaneous reports evidence_span: {"source_cache": "artifacts/sildenafil-research/10078541.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "e65228d2afaad9ce38dccf42c7279ec6b562746aa27b121bf5e5782f36cbe593", "start_char": 0, "end_char": 2772, "text_sha256": "e65228d2afaad9ce38dccf42c7279ec6b562746aa27b121bf5e5782f36cbe593"} [sil-p10078541] Overall cardiovascular profile of sildenafil citrate. (1999). https://pubmed.ncbi.nlm.nih.gov/10078541/ DOI: 10.1016/s0002-9149(99)00046-6

   Complete structured claim and evidence