{"id":"9bffb9e8-1f6a-53f0-9c63-9f2477362ae4","stable_key":"252872b9-233f-5692-b72b-c8930ba0cfb7:sil-inhibition-alone-is-not-enough","predicate":"preserves_measured_pool","statement":"In human platelet extracts PDE2, PDE3 and PDE5 were identified with no PDE1 or PDE4, cyclic GMP hydrolytic activity was about six times higher than cyclic AMP hydrolytic activity, platelets were among the tissues richest in PDE5, and the selective inhibitor E4021 up to 10 micromolar did not inhibit thromboxane-analogue-induced aggregation on its own while E4021 plus the nitric oxide donor SIN-1, at concentrations that had little effect individually, did inhibit aggregation.","claim_class":"observational","status":"source_derived_draft","evidence_grade":"ungraded","direction":"neutral","is_public":true,"mechanism_event_id":"0e7cbf9a-a86f-5291-bb38-99eb0460cd57","mechanism_event_label":"The tissue richest in this enzyme is unaffected by blocking it unless something is making the messenger.","subject":{"id":"7747eb4c-1892-58a2-90c7-e21f146ab5fc","slug":"e4021","display_name":"E4021, a selective PDE5 inhibitor","entity_type_key":"chemical_species"},"object":{"id":"0f8b785e-a816-50a4-84b4-d5aef1ac3fa1","slug":"platelet-aggregation-sil","display_name":"Platelet aggregation","entity_type_key":"cellular_process"},"evidence_count":1,"mechanism_event":{"id":"0e7cbf9a-a86f-5291-bb38-99eb0460cd57","stable_key":"252872b9-233f-5692-b72b-c8930ba0cfb7:sil-inhibition-alone-is-not-enough-event","event_type":"observed_intervention","label":"The tissue richest in this enzyme is unaffected by blocking it unless something is making the messenger.","description":"In human platelet extracts PDE2, PDE3 and PDE5 were identified with no PDE1 or PDE4, cyclic GMP hydrolytic activity was about six times higher than cyclic AMP hydrolytic activity, platelets were among the tissues richest in PDE5, and the selective inhibitor E4021 up to 10 micromolar did not inhibit thromboxane-analogue-induced aggregation on its own while E4021 plus the nitric oxide donor SIN-1, at concentrations that had little effect individually, did inhibit aggregation.","status":"provisional","compartment":null,"participants":[{"entity":{"id":"0be8b435-6b8a-592c-bd4c-c0efd9481a97","slug":"pde5-family","display_name":"Phosphodiesterase 5 family","entity_type_key":"protein_family"},"role":"inhibited_enzyme","stoichiometry":null,"state_label":"","sequence_order":0,"notes":""},{"entity":{"id":"3c107726-27bc-5c22-b2b0-4ee7f9837f7e","slug":"sin-1","display_name":"SIN-1 (3-morpholinosydnonimine)","entity_type_key":"small_molecule"},"role":"required_donor","stoichiometry":null,"state_label":"","sequence_order":1,"notes":""},{"entity":{"id":"3cc7ab30-e6f8-51b9-8979-70f0ea692dc8","slug":"platelet","display_name":"Blood platelet","entity_type_key":"cell_type"},"role":"host_cell","stoichiometry":null,"state_label":"","sequence_order":2,"notes":""},{"entity":{"id":"77d7a14d-d02e-58cb-8fb5-4469f85bb8a5","slug":"pde3","display_name":"Phosphodiesterase 3","entity_type_key":"protein_family"},"role":"co_present_family","stoichiometry":null,"state_label":"","sequence_order":3,"notes":""},{"entity":{"id":"7747eb4c-1892-58a2-90c7-e21f146ab5fc","slug":"e4021","display_name":"E4021, a selective PDE5 inhibitor","entity_type_key":"chemical_species"},"role":"subject","stoichiometry":null,"state_label":"","sequence_order":4,"notes":""},{"entity":{"id":"0f8b785e-a816-50a4-84b4-d5aef1ac3fa1","slug":"platelet-aggregation-sil","display_name":"Platelet aggregation","entity_type_key":"cellular_process"},"role":"target","stoichiometry":null,"state_label":"","sequence_order":5,"notes":""}]},"contexts":[{"dimension":"evidence_span","value_text":"{\"source_cache\": \"artifacts/sildenafil-research/9115850.abstract.txt\", \"locator\": \"Indexed abstract; zero-based, end-exclusive Unicode character offsets\", \"file_sha256\": \"ff6132fc80fceda8601406e8827a621afbb66fb4ebaf2bcd4f722ac875c73a54\", \"start_char\": 0, \"end_char\": 1152, \"text_sha256\": \"ff6132fc80fceda8601406e8827a621afbb66fb4ebaf2bcd4f722ac875c73a54\"}","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"experimental_model","value_text":"Phosphodiesterase isoenzyme separation from human platelet extracts with aggregometry","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"exposure","value_text":"A selective PDE5 inhibitor alone and combined with the nitric oxide donor SIN-1","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"limitations","value_text":"Establishes the enzyme complement of the platelet and tests whether inhibiting it is sufficient. 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It uses E4021 rather than sildenafil, which is recorded on the claim.\nexposure: A selective PDE5 inhibitor alone and combined with the nitric oxide donor SIN-1\nevidence_span: {\"source_cache\": \"artifacts/sildenafil-research/9115850.abstract.txt\", \"locator\": \"Indexed abstract; zero-based, end-exclusive Unicode character offsets\", \"file_sha256\": \"ff6132fc80fceda8601406e8827a621afbb66fb4ebaf2bcd4f722ac875c73a54\", \"start_char\": 0, \"end_char\": 1152, \"text_sha256\": \"ff6132fc80fceda8601406e8827a621afbb66fb4ebaf2bcd4f722ac875c73a54\"}\n[sil-p9115850] Characterization of the isoenzymes of cyclic nucleotide phosphodiesterase in human platelets and the effects of E4021. 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