{"id":"70866e49-2098-54bc-adc0-d1bed32ef29b","stable_key":"252872b9-233f-5692-b72b-c8930ba0cfb7:sil-no-effect-without-nitric-oxide","predicate":"preserves_measured_pool","statement":"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.","claim_class":"mechanistic","status":"source_derived_draft","evidence_grade":"ungraded","direction":"neutral","is_public":true,"mechanism_event_id":"fe124384-485e-501b-a99d-b34ea88a6116","mechanism_event_label":"With no signal present the drug does nothing; its entire action is to keep an existing signal from being cleared.","subject":{"id":"fe62cf8d-5f89-5e19-bc36-03ad3c9063b7","slug":"sildenafil","display_name":"Sildenafil","entity_type_key":"drug"},"object":{"id":"d6335fd1-c450-572e-afa6-a27e80fdd133","slug":"smooth-muscle-relaxation","display_name":"Relaxation of vascular and trabecular smooth muscle","entity_type_key":"cellular_process"},"evidence_count":1,"mechanism_event":{"id":"fe124384-485e-501b-a99d-b34ea88a6116","stable_key":"252872b9-233f-5692-b72b-c8930ba0cfb7:sil-no-effect-without-nitric-oxide-event","event_type":"biochemical_relationship","label":"With no signal present the drug does nothing; its entire action is to keep an existing signal from being cleared.","description":"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.","status":"provisional","compartment":null,"participants":[{"entity":{"id":"c654de33-e457-5ca0-8ee6-9f85cdb01c52","slug":"no-cgmp-pathway","display_name":"The nitric oxide to soluble guanylate cyclase to cyclic GMP pathway","entity_type_key":"cellular_process"},"role":"required_upstream","stoichiometry":null,"state_label":"","sequence_order":0,"notes":""},{"entity":{"id":"6d2f509b-3a5b-5a38-b3e7-b148581edec9","slug":"cgmp","display_name":"Cyclic guanosine monophosphate","entity_type_key":"small_molecule"},"role":"preserved_messenger","stoichiometry":null,"state_label":"","sequence_order":1,"notes":""},{"entity":{"id":"e24cdc15-76b3-5898-a42d-632275759a0b","slug":"sodium-nitroprusside","display_name":"Sodium nitroprusside","entity_type_key":"chemical_species"},"role":"nitric_oxide_donor","stoichiometry":null,"state_label":"","sequence_order":2,"notes":""},{"entity":{"id":"9cc3323e-3a7f-5be5-91ae-78dab284fb81","slug":"cyclic-amp","display_name":"Cyclic adenosine monophosphate","entity_type_key":"small_molecule"},"role":"unaffected_nucleotide","stoichiometry":null,"state_label":"","sequence_order":3,"notes":""},{"entity":{"id":"3a7633ec-a265-5827-988d-eed442633b39","slug":"pde6-family","display_name":"Phosphodiesterase 6 family","entity_type_key":"protein_family"},"role":"least_spared_enzyme","stoichiometry":null,"state_label":"","sequence_order":4,"notes":""},{"entity":{"id":"fe62cf8d-5f89-5e19-bc36-03ad3c9063b7","slug":"sildenafil","display_name":"Sildenafil","entity_type_key":"drug"},"role":"subject","stoichiometry":null,"state_label":"","sequence_order":5,"notes":""},{"entity":{"id":"d6335fd1-c450-572e-afa6-a27e80fdd133","slug":"smooth-muscle-relaxation","display_name":"Relaxation of vascular and trabecular smooth muscle","entity_type_key":"cellular_process"},"role":"target","stoichiometry":null,"state_label":"","sequence_order":6,"notes":""}]},"contexts":[{"dimension":"availability_state","value_text":"biomarker_context","comparator":null,"unit":null,"notes":"Imported condition classification; unverified.","entity":null},{"dimension":"evidence_span","value_text":"{\"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\"}","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"experimental_model","value_text":"Enzyme selectivity panel with isolated tissue, anaesthetised dog haemodynamics and isolated retina","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"exposure","value_text":"Sildenafil with and without nitric oxide drive, and against glyceryl trinitrate, sodium nitroprusside and milrinone","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"limitations","value_text":"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.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"nutrient_topic","value_text":"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.","comparator":null,"unit":null,"notes":"","entity":{"slug":"sildenafil","display_name":"Sildenafil","entity_type_key":"drug"}},{"dimension":"organism","value_text":"Human, rabbit and dog","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"plain_language","value_text":"With no signal present the drug does nothing; its entire action is to keep an existing signal from being cleared.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"primary_references","value_text":"[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","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"tissue_or_cell_type","value_text":"Corpus cavernosum, aorta, cardiac trabeculae and retina","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"trigger_kind","value_text":"biomarker_context","comparator":null,"unit":null,"notes":"Imported condition classification; unverified.","entity":null}],"evidence":[{"id":"215ca405-7f83-50fa-96f0-4fcec2ed7769","evidence_kind":"source_excerpt","locator":"Lines 262-273","start_line":262,"end_line":273,"excerpt":"### sil-no-effect-without-nitric-oxide\nSildenafil 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.\nCondition category: biomarker_context\nnutrient_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.\nplain_language: With no signal present the drug does nothing; its entire action is to keep an existing signal from being cleared.\norganism: Human, rabbit and dog\ntissue_or_cell_type: Corpus cavernosum, aorta, cardiac trabeculae and retina\nexperimental_model: Enzyme selectivity panel with isolated tissue, anaesthetised dog haemodynamics and isolated retina\nlimitations: 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.\nexposure: Sildenafil with and without nitric oxide drive, and against glyceryl trinitrate, sodium nitroprusside and milrinone\nevidence_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\"}\n[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","model_system":"Enzyme selectivity panel with isolated tissue, anaesthetised dog haemodynamics and isolated retina","directness":"author_interpretation","verification_status":"source_derived_draft","notes":"Exact curation-document quotation, not publisher quotation. Study 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","relationship":"supports","weight":1.0,"link_notes":"","source":{"id":"c6c2a590-1f8f-5fac-b2c7-3aae0440b9fd","stable_key":"import-252872b9-233f-5692-b72b-c8930ba0cfb7","title":"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)","document_type":"imported_text","citation_label":"AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text.","file_path":"","sha256":"bc81793d20d20d2eaad9cb530b70695d8d8778a3d7136e24715ac3369b939953","revision_id":"301732e1-2446-5b67-b3bd-580164b85b05","review_status":"unverified_draft","notes":""}}],"relations":[],"conflicts":[{"id":"fd89b711-66d9-5734-8e25-711ec09a1840","title":"Does sildenafil need nitric oxide to do anything?","kind":"contradiction","status":"open","why":"The founding pharmacology states the principle plainly: with no nitric oxide drive the drug had no functional effect on isolated human or rabbit corpus cavernosum, and in the anaesthetised dog it did not raise intracavernosal pressure at all until the pelvic nerve was stimulated. The same pattern holds in platelets, where inhibiting the enzyme alone does not affect aggregation but does in the presence of a nitric oxide donor. Against that, two organ bath studies of human penile and conduit vessels found concentration-dependent relaxation by sildenafil alone that was unaffected by nitric oxide synthase inhibition, and in isolated perfused lung the drug blunted hypoxic pulmonary vasoconstriction in mice lacking endothelial nitric oxide synthase, whose authors concluded that other biochemical sources of cyclic GMP also contribute. The records are reconcilable if the requirement is read correctly: what the drug needs is an ongoing supply of cyclic GMP, not specifically endothelial nitric oxide, and vessels with basal tone or a particulate guanylate cyclase input have such a supply where quiescent cavernosal tissue does not. The organ bath work also used concentrations reaching the micromolar range, far above those that inhibit the enzyme, and in the intact human coronary circulation the drug produced no significant change in resting coronary blood flow, which is what a direct relaxant acting independently of upstream drive would have been expected to change. That reading is a synthesis rather than a measurement, and no record here tests it directly.","resolution":"Unresolved; needs review.","created_at":"2026-09-22 18:28:26","record_type":"conflict","display_label":"Recorded conflict","record_url":"/conflicts/fd89b711-66d9-5734-8e25-711ec09a1840","sides":[{"conflict_id":"fd89b711-66d9-5734-8e25-711ec09a1840","ordinal":0,"label":"With no signal present the drug does nothing; its entire action is to keep an existing signal from being cleared.","revision_id":"301732e1-2446-5b67-b3bd-580164b85b05","start_line":262,"end_line":273,"quote":"### sil-no-effect-without-nitric-oxide\nSildenafil 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.\nCondition category: biomarker_context\nnutrient_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.\nplain_language: With no signal present the drug does nothing; its entire action is to keep an existing signal from being cleared.\norganism: Human, rabbit and dog\ntissue_or_cell_type: Corpus cavernosum, aorta, cardiac trabeculae and retina\nexperimental_model: Enzyme selectivity panel with isolated tissue, anaesthetised dog haemodynamics and isolated retina\nlimitations: 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.\nexposure: Sildenafil with and without nitric oxide drive, and against glyceryl trinitrate, sodium nitroprusside and milrinone\nevidence_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\"}\n[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","source_key":"import-252872b9-233f-5692-b72b-c8930ba0cfb7","source_title":"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)","claim_ids":["70866e49-2098-54bc-adc0-d1bed32ef29b"]},{"conflict_id":"fd89b711-66d9-5734-8e25-711ec09a1840","ordinal":1,"label":"In these vessels the drug relaxed them by itself even with nitric oxide synthesis blocked.","revision_id":"301732e1-2446-5b67-b3bd-580164b85b05","start_line":353,"end_line":364,"quote":"### sil-direct-relaxation-survives-nos-block\nIn 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.\nCondition category: normal\nnutrient_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.\nplain_language: In these vessels the drug relaxed them by itself even with nitric oxide synthesis blocked.\norganism: Human\ntissue_or_cell_type: Penile blood vessels\nexperimental_model: Organ bath studies on penile dorsal arteries and deep dorsal veins from fourteen multiorgan donors\nlimitations: 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.\nexposure: Sildenafil from 1 nanomolar to 3 micromolar on precontracted vessels, with nitric oxide synthase inhibition and electrical field stimulation\nevidence_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\"}\n[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","source_key":"import-252872b9-233f-5692-b72b-c8930ba0cfb7","source_title":"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)","claim_ids":["242db007-b9d6-5798-b845-93a4b8091a93"]},{"conflict_id":"fd89b711-66d9-5734-8e25-711ec09a1840","ordinal":2,"label":"In the living coronary circulation it did not change resting flow, though it improved the reserve the vessels could call on.","revision_id":"301732e1-2446-5b67-b3bd-580164b85b05","start_line":379,"end_line":390,"quote":"### sil-no-change-in-coronary-flow\nIn 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.\nCondition category: normal\nnutrient_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.\nplain_language: In the living coronary circulation it did not change resting flow, though it improved the reserve the vessels could call on.\norganism: Human\ntissue_or_cell_type: Coronary circulation\nexperimental_model: Review of the coronary vascular profile assembled from haemodynamic studies and retrospective analysis of the clinical trial programme\nlimitations: 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.\nexposure: Sildenafil at therapeutic doses in men with coronary heart disease not taking nitrates\nevidence_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\"}\n[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","source_key":"import-252872b9-233f-5692-b72b-c8930ba0cfb7","source_title":"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)","claim_ids":["fd8dcbc2-b759-5193-ae7e-9d3bf6f21a32"]}]},{"id":"b0751349-9a08-5242-8a3f-4b119bbad935","title":"Does sildenafil raise cyclic GMP, or cyclic AMP?","kind":"contradiction","status":"open","why":"The mechanism requires that inhibiting a cyclic-GMP-specific phosphodiesterase raises cyclic GMP and leaves cyclic AMP alone, and one study reports exactly that: the drug selectively increased cyclic GMP in coronary vascular smooth muscle with no change in cyclic AMP, and enhanced nitroprusside-driven cyclic GMP accumulation in rabbit corpus cavernosum without affecting cyclic AMP. A study of isolated human cavernous and cardiac tissue found the opposite pattern, with only a minor effect on cyclic GMP across 0.01 to 1 micromolar and a significant rise in cyclic AMP in both tissues, almost equivalent to milrinone in the cardiac samples, and proposed cross-talk between the pathways. The designs differ in an important way: the studies reporting a cyclic GMP rise supplied nitric oxide drive with a donor, and a phosphodiesterase inhibitor cannot raise a messenger that is not being made, whereas the dissenting study measured accumulation without such drive. Whether the cyclic AMP rise is a genuine second action or an artefact of tissue and conditions is not resolved here, and it is recorded because it was offered as an explanation for cardiovascular effects. One further fact belongs on this disagreement rather than inside either record: the dissenting paper drew a published letter in the same journal from Corbin, Francis and Osterloh, and the first two are the enzymologists whose work on the phosphorylation and allosteric binding of this enzyme is cited elsewhere in this chapter. That letter carries no abstract through any accessed endpoint, so its argument has not been read and is recorded as existing rather than as a refutation.","resolution":"Unresolved; needs review. A published reply by the principal characterisers of the enzyme exists and has not been obtained.","created_at":"2026-09-22 18:28:26","record_type":"conflict","display_label":"Recorded conflict","record_url":"/conflicts/b0751349-9a08-5242-8a3f-4b119bbad935","sides":[{"conflict_id":"b0751349-9a08-5242-8a3f-4b119bbad935","ordinal":0,"label":"With no signal present the drug does nothing; its entire action is to keep an existing signal from being cleared.","revision_id":"301732e1-2446-5b67-b3bd-580164b85b05","start_line":262,"end_line":273,"quote":"### sil-no-effect-without-nitric-oxide\nSildenafil 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.\nCondition category: biomarker_context\nnutrient_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.\nplain_language: With no signal present the drug does nothing; its entire action is to keep an existing signal from being cleared.\norganism: Human, rabbit and dog\ntissue_or_cell_type: Corpus cavernosum, aorta, cardiac trabeculae and retina\nexperimental_model: Enzyme selectivity panel with isolated tissue, anaesthetised dog haemodynamics and isolated retina\nlimitations: 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.\nexposure: Sildenafil with and without nitric oxide drive, and against glyceryl trinitrate, sodium nitroprusside and milrinone\nevidence_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\"}\n[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","source_key":"import-252872b9-233f-5692-b72b-c8930ba0cfb7","source_title":"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)","claim_ids":["70866e49-2098-54bc-adc0-d1bed32ef29b"]},{"conflict_id":"b0751349-9a08-5242-8a3f-4b119bbad935","ordinal":1,"label":"In this tissue the drug barely moved the messenger it targets and raised the other one instead.","revision_id":"301732e1-2446-5b67-b3bd-580164b85b05","start_line":392,"end_line":403,"quote":"### sil-cyclic-amp-rose-instead\nIn 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.\nCondition category: normal\nnutrient_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.\nplain_language: In this tissue the drug barely moved the messenger it targets and raised the other one instead.\norganism: Human\ntissue_or_cell_type: Corpus cavernosum and cardiac muscle\nexperimental_model: Radioimmunoassay of cyclic nucleotide accumulation in isolated human corpus cavernosum and cardiac muscle\nlimitations: 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.\nexposure: Sildenafil from 0.01 to 1 micromolar against sodium nitroprusside, forskolin and milrinone as reference compounds\nevidence_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\"}\n[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","source_key":"import-252872b9-233f-5692-b72b-c8930ba0cfb7","source_title":"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)","claim_ids":["e3c9e0aa-6515-52da-889d-7332c1654cd5"]}]}],"corrections":[],"research":null}