Vascular smooth muscle

Where it participates (unsigned role)

1. Sildenafil from 10 nanomolar to 30 micromolar caused concentration-dependent relaxation in internal mammary arteries, radial arteries and forearm veins with a modest relaxant effect in coronary arteries, amplified the relaxation induced by sodium nitroprusside in all four vessels, and relaxation was unaffected by the nitric oxide synthase inhibitor NG-monomethyl-L-arginine at 100 micromolar, the drug being eight to ten times more potent than zaprinast.

   Sildenafil → Coronary and internal mammary and radial arteries source_derived_draftungraded
   Experimental context and source evidence

   evidence_span

   {"source_cache": "artifacts/sildenafil-research/11081893.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "7425aaede1777ba3689df435384bb535635a8181487b1937154eb635a01c9dbb", "start_char": 0, "end_char": 1602, "text_sha256": "7425aaede1777ba3689df435384bb535635a8181487b1937154eb635a01c9dbb"}

   experimental_model

   Organ bath studies on coronary, internal mammary and radial arteries and forearm veins from sixteen multiorgan donors

   exposure

   Sildenafil from 10 nanomolar to 30 micromolar on precontracted vessels, with nitric oxide synthase inhibition

   limitations

   Extends the same finding to conduit arteries used in bypass surgery. Again the upper concentrations are far above therapeutic and the relaxation in coronary artery was modest.

   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 same direct relaxation appears in the arteries used for bypass grafts, and it too survives blocking nitric oxide synthesis.

   primary_references

   [sil-p11081893] Relaxation induced by cGMP phosphodiesterase inhibitors sildenafil and zaprinast in human vessels. (2000). https://pubmed.ncbi.nlm.nih.gov/11081893/ DOI: 10.1016/s0003-4975(00)01914-7

   tissue_or_cell_type

   Arterial and venous conduits

   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 366–377

   AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Organ bath studies on coronary, internal mammary and radial arteries and forearm veins from sixteen multiorgan donors · source_derived_draft · unverified_draft

   ### sil-conduit-arteries-relax-too Sildenafil from 10 nanomolar to 30 micromolar caused concentration-dependent relaxation in internal mammary arteries, radial arteries and forearm veins with a modest relaxant effect in coronary arteries, amplified the relaxation induced by sodium nitroprusside in all four vessels, and relaxation was unaffected by the nitric oxide synthase inhibitor NG-monomethyl-L-arginine at 100 micromolar, the drug being eight to ten times more potent than zaprinast. 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 same direct relaxation appears in the arteries used for bypass grafts, and it too survives blocking nitric oxide synthesis. organism: Human tissue_or_cell_type: Arterial and venous conduits experimental_model: Organ bath studies on coronary, internal mammary and radial arteries and forearm veins from sixteen multiorgan donors limitations: Extends the same finding to conduit arteries used in bypass surgery. Again the upper concentrations are far above therapeutic and the relaxation in coronary artery was modest. exposure: Sildenafil from 10 nanomolar to 30 micromolar on precontracted vessels, with nitric oxide synthase inhibition evidence_span: {"source_cache": "artifacts/sildenafil-research/11081893.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "7425aaede1777ba3689df435384bb535635a8181487b1937154eb635a01c9dbb", "start_char": 0, "end_char": 1602, "text_sha256": "7425aaede1777ba3689df435384bb535635a8181487b1937154eb635a01c9dbb"} [sil-p11081893] Relaxation induced by cGMP phosphodiesterase inhibitors sildenafil and zaprinast in human vessels. (2000). https://pubmed.ncbi.nlm.nih.gov/11081893/ DOI: 10.1016/s0003-4975(00)01914-7

   Complete structured claim and evidence

2. Prior incubation of recombinant phosphodiesterase type 5 with protein kinase G, magnesium ATP and cyclic GMP, producing serine 92 phosphorylation, caused a 50 to 70% increase in enzyme activity and increased the affinity of cyclic GMP binding to the allosteric sites, reducing the concentration needed for half-maximum allosteric binding from 0.13 to 0.03 micromolar, with stimulation obtained at 0.2 to 0.5 micromolar kinase subunit which is approximately the cellular level in vascular smooth muscle, while considerably higher concentrations of protein kinase A were required.

   cGMP-dependent protein kinase I → Phosphodiesterase 5 family source_derived_draftungraded
   Experimental context and source evidence

   evidence_span

   {"source_cache": "artifacts/sildenafil-research/10785399.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "d4048089a01ed860c8a71d096eb5bf1407e19557ca97c88b6cbac0e5f69de171", "start_char": 0, "end_char": 2100, "text_sha256": "d4048089a01ed860c8a71d096eb5bf1407e19557ca97c88b6cbac0e5f69de171"}

   experimental_model

   Phosphorylation of recombinant bovine phosphodiesterase type 5 at serine 92 with activity and binding measurement

   exposure

   Protein kinase G or the catalytic subunit of protein kinase A with magnesium ATP and cyclic GMP

   limitations

   Establishes the feedback loop and shows the kinase concentrations are physiological. It also records that phosphorylation does not change the potency of the drug, which matters for whether the loop blunts the drug.

   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

   Cattle enzyme

   plain_language

   The messenger switches on a kinase that speeds up the enzyme destroying it, which is a brake the cell applies to itself.

   primary_references

   [sil-p10785399] Phosphorylation of phosphodiesterase-5 by cyclic nucleotide-dependent protein kinase alters its catalytic and allosteric cGMP-binding activities. (2000). https://pubmed.ncbi.nlm.nih.gov/10785399/ DOI: 10.1046/j.1432-1327.2000.01297.x

   tissue_or_cell_type

   Recombinant enzyme and lung extract

   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 197–208

   AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Phosphorylation of recombinant bovine phosphodiesterase type 5 at serine 92 with activity and binding measurement · source_derived_draft · unverified_draft

   ### sil-pkg-feedback-speeds-the-enzyme Prior incubation of recombinant phosphodiesterase type 5 with protein kinase G, magnesium ATP and cyclic GMP, producing serine 92 phosphorylation, caused a 50 to 70% increase in enzyme activity and increased the affinity of cyclic GMP binding to the allosteric sites, reducing the concentration needed for half-maximum allosteric binding from 0.13 to 0.03 micromolar, with stimulation obtained at 0.2 to 0.5 micromolar kinase subunit which is approximately the cellular level in vascular smooth muscle, while considerably higher concentrations of protein kinase A were required. 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 messenger switches on a kinase that speeds up the enzyme destroying it, which is a brake the cell applies to itself. organism: Cattle enzyme tissue_or_cell_type: Recombinant enzyme and lung extract experimental_model: Phosphorylation of recombinant bovine phosphodiesterase type 5 at serine 92 with activity and binding measurement limitations: Establishes the feedback loop and shows the kinase concentrations are physiological. It also records that phosphorylation does not change the potency of the drug, which matters for whether the loop blunts the drug. exposure: Protein kinase G or the catalytic subunit of protein kinase A with magnesium ATP and cyclic GMP evidence_span: {"source_cache": "artifacts/sildenafil-research/10785399.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "d4048089a01ed860c8a71d096eb5bf1407e19557ca97c88b6cbac0e5f69de171", "start_char": 0, "end_char": 2100, "text_sha256": "d4048089a01ed860c8a71d096eb5bf1407e19557ca97c88b6cbac0e5f69de171"} [sil-p10785399] Phosphorylation of phosphodiesterase-5 by cyclic nucleotide-dependent protein kinase alters its catalytic and allosteric cGMP-binding activities. (2000). https://pubmed.ncbi.nlm.nih.gov/10785399/ DOI: 10.1046/j.1432-1327.2000.01297.x

   Complete structured claim and evidence

3. PDE5 immunoreactivity was localized to smooth muscle cells in the medial layer of pulmonary arteries and veins in the normal rat lung and in distal muscularized arteries under 25 micrometres in diameter after hypoxia-induced pulmonary hypertension, sildenafil at 25 or 75 milligrams per kilogram per day given before hypoxia produced marked dose-dependent inhibition in the rise of pulmonary artery pressure of 60 to 90% and a 28.4% reduction in vascular muscularization, and when begun after 14 days of hypoxia it significantly reduced pulmonary artery pressure by 30% and partially reversed pulmonary artery muscularization by 39.9%.

   Sildenafil → Pulmonary vascular remodelling source_derived_draftungraded
   Experimental context and source evidence

   evidence_span

   {"source_cache": "artifacts/sildenafil-research/12796132.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "61d9020b6275a7c57fcee753c74b06c334ad034286eeaccdcbdf12e49b472122", "start_char": 0, "end_char": 1616, "text_sha256": "61d9020b6275a7c57fcee753c74b06c334ad034286eeaccdcbdf12e49b472122"}

   experimental_model

   Continuous telemetric pulmonary artery pressure measurement with immunolocalisation and morphometry in rats exposed to hypoxia for up to 42 days

   exposure

   Sildenafil 25 or 75 milligrams per kilogram per day started before hypoxia, or started after 14 days of established pulmonary hypertension

   limitations

   The delayed-treatment arm is what distinguishes prevention from reversal. A rat hypoxia model, and the reversal of muscularisation is partial.

   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

   Rat

   plain_language

   Started after the damage was already there, it still pushed the pressure down and partly undid the thickening.

   primary_references

   [sil-p12796132] Phosphodiesterase type 5 as a target for the treatment of hypoxia-induced pulmonary hypertension. (2003). https://pubmed.ncbi.nlm.nih.gov/12796132/ DOI: 10.1161/01.cir.0000074226.20466.b1

   tissue_or_cell_type

   Pulmonary vascular tree

   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 561–572

   AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Continuous telemetric pulmonary artery pressure measurement with immunolocalisation and morphometry in rats exposed to hypoxia for up to 42 days · source_derived_draft · unverified_draft

   ### sil-reverses-established-remodelling PDE5 immunoreactivity was localized to smooth muscle cells in the medial layer of pulmonary arteries and veins in the normal rat lung and in distal muscularized arteries under 25 micrometres in diameter after hypoxia-induced pulmonary hypertension, sildenafil at 25 or 75 milligrams per kilogram per day given before hypoxia produced marked dose-dependent inhibition in the rise of pulmonary artery pressure of 60 to 90% and a 28.4% reduction in vascular muscularization, and when begun after 14 days of hypoxia it significantly reduced pulmonary artery pressure by 30% and partially reversed pulmonary artery muscularization by 39.9%. 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: Started after the damage was already there, it still pushed the pressure down and partly undid the thickening. organism: Rat tissue_or_cell_type: Pulmonary vascular tree experimental_model: Continuous telemetric pulmonary artery pressure measurement with immunolocalisation and morphometry in rats exposed to hypoxia for up to 42 days limitations: The delayed-treatment arm is what distinguishes prevention from reversal. A rat hypoxia model, and the reversal of muscularisation is partial. exposure: Sildenafil 25 or 75 milligrams per kilogram per day started before hypoxia, or started after 14 days of established pulmonary hypertension evidence_span: {"source_cache": "artifacts/sildenafil-research/12796132.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "61d9020b6275a7c57fcee753c74b06c334ad034286eeaccdcbdf12e49b472122", "start_char": 0, "end_char": 1616, "text_sha256": "61d9020b6275a7c57fcee753c74b06c334ad034286eeaccdcbdf12e49b472122"} [sil-p12796132] Phosphodiesterase type 5 as a target for the treatment of hypoxia-induced pulmonary hypertension. (2003). https://pubmed.ncbi.nlm.nih.gov/12796132/ DOI: 10.1161/01.cir.0000074226.20466.b1

   Complete structured claim and evidence