Phosphodiesterase 3

Where it participates (unsigned role)

1. 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.

   E4021, a selective PDE5 inhibitor → Platelet aggregation source_derived_draftungraded
   Experimental context and source evidence

   evidence_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"}

   experimental_model

   Phosphodiesterase isoenzyme separation from human platelet extracts with aggregometry

   exposure

   A selective PDE5 inhibitor alone and combined with the nitric oxide donor SIN-1

   limitations

   Establishes the enzyme complement of the platelet and tests whether inhibiting it is sufficient. It uses E4021 rather than sildenafil, which is recorded on the claim.

   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

   The tissue richest in this enzyme is unaffected by blocking it unless something is making the messenger.

   primary_references

   [sil-p9115850] Characterization of the isoenzymes of cyclic nucleotide phosphodiesterase in human platelets and the effects of E4021. (1996). https://pubmed.ncbi.nlm.nih.gov/9115850/ DOI: 10.1016/s0898-6568(96)00112-x

   tissue_or_cell_type

   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 340–351

   AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Phosphodiesterase isoenzyme separation from human platelet extracts with aggregometry · source_derived_draft · unverified_draft

   ### sil-inhibition-alone-is-not-enough 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. 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: The tissue richest in this enzyme is unaffected by blocking it unless something is making the messenger. organism: Human tissue_or_cell_type: Platelets experimental_model: Phosphodiesterase isoenzyme separation from human platelet extracts with aggregometry limitations: Establishes the enzyme complement of the platelet and tests whether inhibiting it is sufficient. It uses E4021 rather than sildenafil, which is recorded on the claim. exposure: A selective PDE5 inhibitor alone and combined with the nitric oxide donor SIN-1 evidence_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"} [sil-p9115850] Characterization of the isoenzymes of cyclic nucleotide phosphodiesterase in human platelets and the effects of E4021. (1996). https://pubmed.ncbi.nlm.nih.gov/9115850/ DOI: 10.1016/s0898-6568(96)00112-x

   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. Both cyclic GMP and cyclic AMP specific phosphodiesterases were identified in human corpora cavernosa in vitro, the main phosphodiesterase activity in this tissue being due to PDE5 with PDE2 and PDE3 also identified, and sildenafil is a selective inhibitor of PDE5 with a mean half-maximal inhibitory concentration of 0.0039 micromolar.

   Phosphodiesterase 5 family → Human corpus cavernosum trabecular smooth muscle source_derived_draftungraded
   Experimental context and source evidence

   evidence_span

   {"source_cache": "artifacts/sildenafil-research/8858389.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "173f69debd8427b8a1c001e543e4356f2d3b90c730ca3217073a25c4bc61905a", "start_char": 0, "end_char": 1288, "text_sha256": "173f69debd8427b8a1c001e543e4356f2d3b90c730ca3217073a25c4bc61905a"}

   experimental_model

   Phosphodiesterase isozyme characterisation in human corpora cavernosa with volunteer pharmacokinetics and a small clinical study

   exposure

   Sildenafil assayed against phosphodiesterase isozymes prepared from human tissue

   limitations

   The first report of the compound. The clinical arm is twelve patients without an established organic cause, so it establishes the target rather than the treatment 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

   One of the several enzymes in this tissue carries most of the activity, and the drug was built against that one.

   primary_references

   [sil-p8858389] Sildenafil: an orally active type 5 cyclic GMP-specific phosphodiesterase inhibitor for the treatment of penile erectile dysfunction. (1996). https://pubmed.ncbi.nlm.nih.gov/8858389/

   tissue_or_cell_type

   Corpus cavernosum

   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 119–130

   AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Phosphodiesterase isozyme characterisation in human corpora cavernosa with volunteer pharmacokinetics and a small clinical study · source_derived_draft · unverified_draft

   ### sil-pde5-is-the-main-isozyme Both cyclic GMP and cyclic AMP specific phosphodiesterases were identified in human corpora cavernosa in vitro, the main phosphodiesterase activity in this tissue being due to PDE5 with PDE2 and PDE3 also identified, and sildenafil is a selective inhibitor of PDE5 with a mean half-maximal inhibitory concentration of 0.0039 micromolar. 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: One of the several enzymes in this tissue carries most of the activity, and the drug was built against that one. organism: Human tissue_or_cell_type: Corpus cavernosum experimental_model: Phosphodiesterase isozyme characterisation in human corpora cavernosa with volunteer pharmacokinetics and a small clinical study limitations: The first report of the compound. The clinical arm is twelve patients without an established organic cause, so it establishes the target rather than the treatment effect. exposure: Sildenafil assayed against phosphodiesterase isozymes prepared from human tissue evidence_span: {"source_cache": "artifacts/sildenafil-research/8858389.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "173f69debd8427b8a1c001e543e4356f2d3b90c730ca3217073a25c4bc61905a", "start_char": 0, "end_char": 1288, "text_sha256": "173f69debd8427b8a1c001e543e4356f2d3b90c730ca3217073a25c4bc61905a"} [sil-p8858389] Sildenafil: an orally active type 5 cyclic GMP-specific phosphodiesterase inhibitor for the treatment of penile erectile dysfunction. (1996). https://pubmed.ncbi.nlm.nih.gov/8858389/

   Complete structured claim and evidence