{"id":"e3c9e0aa-6515-52da-889d-7332c1654cd5","stable_key":"252872b9-233f-5692-b72b-c8930ba0cfb7:sil-cyclic-amp-rose-instead","predicate":"increases","statement":"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.","claim_class":"observational","status":"source_derived_draft","evidence_grade":"ungraded","direction":"positive","is_public":true,"mechanism_event_id":"1453def8-5ec6-5883-9f3f-85ddec150af0","mechanism_event_label":"In this tissue the drug barely moved the messenger it targets and raised the other one instead.","subject":{"id":"fe62cf8d-5f89-5e19-bc36-03ad3c9063b7","slug":"sildenafil","display_name":"Sildenafil","entity_type_key":"drug"},"object":{"id":"9cc3323e-3a7f-5be5-91ae-78dab284fb81","slug":"cyclic-amp","display_name":"Cyclic adenosine monophosphate","entity_type_key":"small_molecule"},"evidence_count":1,"mechanism_event":{"id":"1453def8-5ec6-5883-9f3f-85ddec150af0","stable_key":"252872b9-233f-5692-b72b-c8930ba0cfb7:sil-cyclic-amp-rose-instead-event","event_type":"observed_intervention","label":"In this tissue the drug barely moved the messenger it targets and raised the other one instead.","description":"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.","status":"provisional","compartment":null,"participants":[{"entity":{"id":"6d2f509b-3a5b-5a38-b3e7-b148581edec9","slug":"cgmp","display_name":"Cyclic guanosine monophosphate","entity_type_key":"small_molecule"},"role":"barely_changed_nucleotide","stoichiometry":null,"state_label":"","sequence_order":0,"notes":""},{"entity":{"id":"29046ffa-33dc-5638-8cca-485561a2ddb1","slug":"milrinone","display_name":"Milrinone, a phosphodiesterase 3 inhibitor","entity_type_key":"drug"},"role":"comparator_drug","stoichiometry":null,"state_label":"","sequence_order":1,"notes":""},{"entity":{"id":"0aaf2654-17b5-57f9-b3ca-5db8b3229b53","slug":"cyclic-nucleotide-crosstalk","display_name":"Cross-talk between cyclic GMP and cyclic AMP signalling","entity_type_key":"cellular_process"},"role":"proposed_mechanism","stoichiometry":null,"state_label":"","sequence_order":2,"notes":""},{"entity":{"id":"cb499151-ca3f-5526-97fa-4480ac2de9c0","slug":"cardiac-ventricle","display_name":"Human cardiac ventricle","entity_type_key":"tissue"},"role":"test_tissue","stoichiometry":null,"state_label":"","sequence_order":3,"notes":""},{"entity":{"id":"cbc3040f-2766-5395-bc04-81e2aeb9dc87","slug":"corpus-cavernosum","display_name":"Human corpus cavernosum trabecular smooth muscle","entity_type_key":"tissue"},"role":"test_tissue","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":"9cc3323e-3a7f-5be5-91ae-78dab284fb81","slug":"cyclic-amp","display_name":"Cyclic adenosine monophosphate","entity_type_key":"small_molecule"},"role":"target","stoichiometry":null,"state_label":"","sequence_order":6,"notes":""}]},"contexts":[{"dimension":"evidence_span","value_text":"{\"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\"}","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"experimental_model","value_text":"Radioimmunoassay of cyclic nucleotide accumulation in isolated human corpus cavernosum and cardiac muscle","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"exposure","value_text":"Sildenafil from 0.01 to 1 micromolar against sodium nitroprusside, forskolin and milrinone as reference compounds","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"limitations","value_text":"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.","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","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"plain_language","value_text":"In this tissue the drug barely moved the messenger it targets and raised the other one instead.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"primary_references","value_text":"[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","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"tissue_or_cell_type","value_text":"Corpus cavernosum and cardiac muscle","comparator":null,"unit":null,"notes":"","entity":null}],"evidence":[{"id":"59122059-4c1d-512c-9df6-42558dcb323b","evidence_kind":"source_excerpt","locator":"Lines 392-403","start_line":392,"end_line":403,"excerpt":"### 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","model_system":"Radioimmunoassay of cyclic nucleotide accumulation in isolated human corpus cavernosum and cardiac muscle","directness":"author_interpretation","verification_status":"source_derived_draft","notes":"Exact curation-document quotation, not publisher quotation. Study 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","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":"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. 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