Nitroglycerin

Where it participates (unsigned role)

1. During treatment with sildenafil 25 milligrams three times daily subjects were significantly less tolerant of intravenously administered glyceryl trinitrate than during placebo based on the occurrence of a greater than 25 millimetre fall in blood pressure or symptomatic hypotension, and when a 500 microgram sublingual glyceryl trinitrate tablet was administered a fourfold greater decrease in systolic blood pressure was observed during the sildenafil period than during placebo, with negligible changes in heart rate, so that administration to patients using organic nitrates in any form is contraindicated.

   Sildenafil → Potentiation of the hypotensive effect of an organic nitrate source_derived_draftungraded
   Experimental context and source evidence

   availability_state

   biomarker_context Imported condition classification; unverified.

   evidence_span

   {"source_cache": "artifacts/sildenafil-research/10078539.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "469d3f90cc5be3f1c0ef247d099fa70d81aa953b8a6b33334abc38d34f346654", "start_char": 0, "end_char": 3999, "text_sha256": "469d3f90cc5be3f1c0ef247d099fa70d81aa953b8a6b33334abc38d34f346654"}

   experimental_model

   Double-blind placebo-controlled crossover studies of nitrate and calcium antagonist coadministration in healthy men and men with hypertension

   exposure

   Sildenafil 25 milligrams three times daily with stepwise intravenous and sublingual glyceryl trinitrate, and a single 100 milligram dose with amlodipine

   limitations

   The design that establishes the contraindication, and the amlodipine arm is the control that shows it is specific to the shared pathway rather than additive antihypertensive effect.

   nutrient_topic

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

   organism

   Human

   plain_language

   On this drug a standard nitrate tablet dropped blood pressure four times as far.

   primary_references

   [sil-p10078539] Sildenafil citrate and blood-pressure-lowering drugs: results of drug interaction studies with an organic nitrate and a calcium antagonist. (1999). https://pubmed.ncbi.nlm.nih.gov/10078539/ DOI: 10.1016/s0002-9149(99)00044-2

   tissue_or_cell_type

   Systemic circulation

   trigger_kind

   biomarker_context Imported condition classification; unverified.

   Sildenafil: the enzyme it occupies instead of the substrate, why it cannot start a signal it can only preserve, the organic nitrate interaction that follows from that, the homologous retinal enzyme ten-fold away, and the pulmonary circulation where the same mechanism became a second indication (2026-09-22) · lines 405–416

   AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Double-blind placebo-controlled crossover studies of nitrate and calcium antagonist coadministration in healthy men and men with hypertension · source_derived_draft · unverified_draft

   ### sil-nitrate-potentiation-fourfold During treatment with sildenafil 25 milligrams three times daily subjects were significantly less tolerant of intravenously administered glyceryl trinitrate than during placebo based on the occurrence of a greater than 25 millimetre fall in blood pressure or symptomatic hypotension, and when a 500 microgram sublingual glyceryl trinitrate tablet was administered a fourfold greater decrease in systolic blood pressure was observed during the sildenafil period than during placebo, with negligible changes in heart rate, so that administration to patients using organic nitrates in any form is contraindicated. Condition category: biomarker_context nutrient_topic: Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. plain_language: On this drug a standard nitrate tablet dropped blood pressure four times as far. organism: Human tissue_or_cell_type: Systemic circulation experimental_model: Double-blind placebo-controlled crossover studies of nitrate and calcium antagonist coadministration in healthy men and men with hypertension limitations: The design that establishes the contraindication, and the amlodipine arm is the control that shows it is specific to the shared pathway rather than additive antihypertensive effect. exposure: Sildenafil 25 milligrams three times daily with stepwise intravenous and sublingual glyceryl trinitrate, and a single 100 milligram dose with amlodipine evidence_span: {"source_cache": "artifacts/sildenafil-research/10078539.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "469d3f90cc5be3f1c0ef247d099fa70d81aa953b8a6b33334abc38d34f346654", "start_char": 0, "end_char": 3999, "text_sha256": "469d3f90cc5be3f1c0ef247d099fa70d81aa953b8a6b33334abc38d34f346654"} [sil-p10078539] Sildenafil citrate and blood-pressure-lowering drugs: results of drug interaction studies with an organic nitrate and a calcium antagonist. (1999). https://pubmed.ncbi.nlm.nih.gov/10078539/ DOI: 10.1016/s0002-9149(99)00044-2

   Complete structured claim and evidence

2. Unlike milrinone, sildenafil had no inotropic effects on dog isolated trabeculae carneae so it is unlikely to have the deleterious effects on cardiac function associated with PDE3 inhibitors, while consistent with its mode of action it potentiated the vasorelaxant effects of glyceryl trinitrate on rabbit isolated aortic rings.

   Sildenafil → Myocardial inotropic response source_derived_draftungraded
   Experimental context and source evidence

   evidence_span

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

   experimental_model

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

   exposure

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

   limitations

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

   nutrient_topic

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

   organism

   Human, rabbit and dog

   plain_language

   It leaves the heart muscle alone, unlike the drugs that block a different member of the same enzyme family.

   primary_references

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

   tissue_or_cell_type

   Corpus cavernosum, aorta, cardiac trabeculae and retina

   Sildenafil: the enzyme it occupies instead of the substrate, why it cannot start a signal it can only preserve, the organic nitrate interaction that follows from that, the homologous retinal enzyme ten-fold away, and the pulmonary circulation where the same mechanism became a second indication (2026-09-22) · lines 275–286

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

   ### sil-no-inotropic-effect Unlike milrinone, sildenafil had no inotropic effects on dog isolated trabeculae carneae so it is unlikely to have the deleterious effects on cardiac function associated with PDE3 inhibitors, while consistent with its mode of action it potentiated the vasorelaxant effects of glyceryl trinitrate on rabbit isolated aortic rings. Condition category: normal nutrient_topic: Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. plain_language: It leaves the heart muscle alone, unlike the drugs that block a different member of the same enzyme family. organism: Human, rabbit and dog tissue_or_cell_type: Corpus cavernosum, aorta, cardiac trabeculae and retina experimental_model: Enzyme selectivity panel with isolated tissue, anaesthetised dog haemodynamics and isolated retina limitations: The single most complete pharmacological characterisation here, covering the target, the absence of effect without upstream drive, the nitrate potentiation, the absence of an inotropic effect, and the retinal effect in one series. exposure: Sildenafil with and without nitric oxide drive, and against glyceryl trinitrate, sodium nitroprusside and milrinone evidence_span: {"source_cache": "artifacts/sildenafil-research/10629850.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "af056c516b44e35eac7b0511ba3a8403ed84c347af6094ebc153f68c8ee7db92", "start_char": 0, "end_char": 2057, "text_sha256": "af056c516b44e35eac7b0511ba3a8403ed84c347af6094ebc153f68c8ee7db92"} [sil-p10629850] The pharmacology of sildenafil, a novel and selective inhibitor of phosphodiesterase (PDE) type 5. (1999). https://pubmed.ncbi.nlm.nih.gov/10629850/ DOI: 10.1254/fpj.114.supplement_22

   Complete structured claim and evidence

3. Human platelets were found to contain PDE5 which was inhibited by sildenafil with a half-maximal inhibitory concentration of 6.3 nanomolar consistent with the value in corpus cavernosum, sildenafil alone had no direct effect on platelet function but it potentiated the in vitro antiaggregatory activity of sodium nitroprusside on rabbit and human platelets, and in phenylephrine-contracted rabbit aortic rings it enhanced glyceryl trinitrate relaxation.

   Sildenafil → Platelet aggregation source_derived_draftungraded
   Experimental context and source evidence

   evidence_span

   {"source_cache": "artifacts/sildenafil-research/10078537.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "dceb60af4400fe67b4ffaf73a0aadb8d2e5fad0966b3372a3e46a91c0e0ccee5", "start_char": 0, "end_char": 2610, "text_sha256": "dceb60af4400fe67b4ffaf73a0aadb8d2e5fad0966b3372a3e46a91c0e0ccee5"}

   experimental_model

   Immunochemical distribution of phosphodiesterase activity across human tissues with isolated organ bath studies and platelet aggregometry

   exposure

   Anti-PDE1 and anti-PDE5 antibodies with functional testing, and sildenafil against sodium nitroprusside on platelets

   limitations

   Maps where the target enzyme is and is not, which is what predicts where the drug acts. Antibody-based detection, so absence of signal is weaker evidence than presence.

   nutrient_topic

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

   organism

   Human, rabbit and dog

   plain_language

   Platelets carry the same enzyme, and again the drug does nothing to them until a nitric oxide donor is present.

   primary_references

   [sil-p10078537] Tissue distribution of phosphodiesterase families and the effects of sildenafil on tissue cyclic nucleotides, platelet function, and the contractile responses of trabeculae carneae and aortic rings in vitro. (1999). https://pubmed.ncbi.nlm.nih.gov/10078537/ DOI: 10.1016/s0002-9149(99)00042-9

   tissue_or_cell_type

   Cardiac ventricle, saphenous vein, mesenteric artery, corpus cavernosum and platelets

   Sildenafil: the enzyme it occupies instead of the substrate, why it cannot start a signal it can only preserve, the organic nitrate interaction that follows from that, the homologous retinal enzyme ten-fold away, and the pulmonary circulation where the same mechanism became a second indication (2026-09-22) · lines 327–338

   AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Immunochemical distribution of phosphodiesterase activity across human tissues with isolated organ bath studies and platelet aggregometry · source_derived_draft · unverified_draft

   ### sil-platelets-need-a-donor-too Human platelets were found to contain PDE5 which was inhibited by sildenafil with a half-maximal inhibitory concentration of 6.3 nanomolar consistent with the value in corpus cavernosum, sildenafil alone had no direct effect on platelet function but it potentiated the in vitro antiaggregatory activity of sodium nitroprusside on rabbit and human platelets, and in phenylephrine-contracted rabbit aortic rings it enhanced glyceryl trinitrate relaxation. Condition category: normal nutrient_topic: Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. plain_language: Platelets carry the same enzyme, and again the drug does nothing to them until a nitric oxide donor is present. organism: Human, rabbit and dog tissue_or_cell_type: Cardiac ventricle, saphenous vein, mesenteric artery, corpus cavernosum and platelets experimental_model: Immunochemical distribution of phosphodiesterase activity across human tissues with isolated organ bath studies and platelet aggregometry limitations: Maps where the target enzyme is and is not, which is what predicts where the drug acts. Antibody-based detection, so absence of signal is weaker evidence than presence. exposure: Anti-PDE1 and anti-PDE5 antibodies with functional testing, and sildenafil against sodium nitroprusside on platelets evidence_span: {"source_cache": "artifacts/sildenafil-research/10078537.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "dceb60af4400fe67b4ffaf73a0aadb8d2e5fad0966b3372a3e46a91c0e0ccee5", "start_char": 0, "end_char": 2610, "text_sha256": "dceb60af4400fe67b4ffaf73a0aadb8d2e5fad0966b3372a3e46a91c0e0ccee5"} [sil-p10078537] Tissue distribution of phosphodiesterase families and the effects of sildenafil on tissue cyclic nucleotides, platelet function, and the contractile responses of trabeculae carneae and aortic rings in vitro. (1999). https://pubmed.ncbi.nlm.nih.gov/10078537/ DOI: 10.1016/s0002-9149(99)00042-9

   Complete structured claim and evidence

4. After tadalafil, sublingual nitroglycerin lowered standing systolic blood pressure below 85 mmHg in more subjects than after placebo at 4, 8 and 24 hours, with no difference at 48, 72 and 96 hours.

   Tadalafil → Standing systolic blood pressure source_derived_draftungraded
   Experimental context and source evidence

   duration

   Measured to 96 hours after the last tadalafil dose

   evidence_access

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

   experimental_model

   150 male subjects, randomised crossover with a 10 to 21 day washout

   exposure

   Seven consecutive daily doses of tadalafil 20 mg or placebo, then repeated sublingual nitroglycerin 0.4 mg

   limitations

   A pharmacodynamic interaction study in male volunteers using a fixed 20 mg dose; the time course reported here describes when the interaction was detectable, not a dosing instruction.

   organism

   150 male subjects, randomised crossover with a 10 to 21 day washout

   plain_language

   After tadalafil, sublingual nitroglycerin lowered standing systolic blood pressure below 85 mmHg in more subjects than after placebo at 4, 8 and 24 hours, with no difference at 48, 72 and 96 hours.

   primary_references

   Time course of the interaction between tadalafil and nitrates. (2003). https://pubmed.ncbi.nlm.nih.gov/14642699/ DOI: 10.1016/j.jacc.2003.09.023

   route

   Oral tadalafil with sublingual nitroglycerin

   tissue

   Standing systolic and diastolic blood pressure after a nitrate

   Tadalafil: PDE5 occupancy, the cGMP route and three measured endpoints (2026-09-22) · lines 89–98

   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-augments-the-nitrate-blood-pressure-fall After tadalafil, sublingual nitroglycerin lowered standing systolic blood pressure below 85 mmHg in more subjects than after placebo at 4, 8 and 24 hours, with no difference at 48, 72 and 96 hours. Model/species: 150 male subjects, randomised crossover with a 10 to 21 day washout Tissue/system: Standing systolic and diastolic blood pressure after a nitrate Exposure: Seven consecutive daily doses of tadalafil 20 mg or placebo, then repeated sublingual nitroglycerin 0.4 mg Route: Oral tadalafil with sublingual nitroglycerin Duration: Measured to 96 hours after the last tadalafil dose Limits: A pharmacodynamic interaction study in male volunteers using a fixed 20 mg dose; the time course reported here describes when the interaction was detectable, not a dosing instruction. Primary reference: Time course of the interaction between tadalafil and nitrates. (2003). https://pubmed.ncbi.nlm.nih.gov/14642699/ DOI: 10.1016/j.jacc.2003.09.023 Access: Primary PubMed abstract and indexed metadata reviewed. Full-text method details not stated here remain unresolved.

   Complete structured claim and evidence