Hydrolysis of cyclic GMP to 5-guanosine monophosphate

Where it participates (unsigned role)

1. The newly cloned phosphodiesterase PDE9A1 is highly specific for cyclic GMP with a Michaelis constant of approximately 0.07 micromolar, the lowest yet reported for a phosphodiesterase and at least 40 to 170 times lower than that of PDE5 and PDE6 respectively, it shows highest messenger RNA expression in kidney with lower levels in liver, lung and brain, and when expressed in COS-7 cells its activity was not inhibited well by either the nonselective inhibitor 3-isobutyl-1-methylxanthine or the new selective PDE5 inhibitor sildenafil, while the PDE1 and PDE5 inhibitor SCH51866 inhibited it with a half-maximal concentration of 1.55 micromolar.

   Sildenafil → Phosphodiesterase 9A source_derived_draftungraded
   Experimental context and source evidence

   evidence_span

   {"source_cache": "artifacts/sildenafil-research/9624145.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "ea6afcfbb102bf5a407894b06969c9fe245261fa8a1fea8fb92b201d8b24ace2", "start_char": 0, "end_char": 1265, "text_sha256": "ea6afcfbb102bf5a407894b06969c9fe245261fa8a1fea8fb92b201d8b24ace2"}

   experimental_model

   Cloning, expression and kinetic characterisation of a newly identified cyclic nucleotide phosphodiesterase family

   exposure

   Recombinant PDE9A1 against 3-isobutyl-1-methylxanthine, sildenafil and SCH51866

   limitations

   A cloning and characterisation report. The expression survey is messenger RNA rather than protein, and the enzyme is heterologously expressed.

   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

   Mouse

   plain_language

   There is another enzyme that destroys the same messenger even more avidly, and this drug does not touch it.

   primary_references

   [sil-p9624145] Identification and characterization of a novel family of cyclic nucleotide phosphodiesterases. (1998). https://pubmed.ncbi.nlm.nih.gov/9624145/ DOI: 10.1074/jbc.273.25.15553

   tissue_or_cell_type

   Kidney, liver, lung and brain messenger RNA

   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 236–247

   AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Cloning, expression and kinetic characterisation of a newly identified cyclic nucleotide phosphodiesterase family · source_derived_draft · unverified_draft

   ### sil-another-cgmp-enzyme-it-misses The newly cloned phosphodiesterase PDE9A1 is highly specific for cyclic GMP with a Michaelis constant of approximately 0.07 micromolar, the lowest yet reported for a phosphodiesterase and at least 40 to 170 times lower than that of PDE5 and PDE6 respectively, it shows highest messenger RNA expression in kidney with lower levels in liver, lung and brain, and when expressed in COS-7 cells its activity was not inhibited well by either the nonselective inhibitor 3-isobutyl-1-methylxanthine or the new selective PDE5 inhibitor sildenafil, while the PDE1 and PDE5 inhibitor SCH51866 inhibited it with a half-maximal concentration of 1.55 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: There is another enzyme that destroys the same messenger even more avidly, and this drug does not touch it. organism: Mouse tissue_or_cell_type: Kidney, liver, lung and brain messenger RNA experimental_model: Cloning, expression and kinetic characterisation of a newly identified cyclic nucleotide phosphodiesterase family limitations: A cloning and characterisation report. The expression survey is messenger RNA rather than protein, and the enzyme is heterologously expressed. exposure: Recombinant PDE9A1 against 3-isobutyl-1-methylxanthine, sildenafil and SCH51866 evidence_span: {"source_cache": "artifacts/sildenafil-research/9624145.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "ea6afcfbb102bf5a407894b06969c9fe245261fa8a1fea8fb92b201d8b24ace2", "start_char": 0, "end_char": 1265, "text_sha256": "ea6afcfbb102bf5a407894b06969c9fe245261fa8a1fea8fb92b201d8b24ace2"} [sil-p9624145] Identification and characterization of a novel family of cyclic nucleotide phosphodiesterases. (1998). https://pubmed.ncbi.nlm.nih.gov/9624145/ DOI: 10.1074/jbc.273.25.15553

   Complete structured claim and evidence

2. Cyclic GMP and its primary signalling kinase protein kinase G play a role in counterbalancing stress remodelling in the heart, growing evidence supports a positive impact on a variety of cardiac disease conditions from suppression of cyclic GMP hydrolysis which is regulated by phosphodiesterase family members of which cyclic-GMP-selective PDE5 has been best studied, and inhibitors such as sildenafil and tadalafil ameliorate cardiac pressure and volume overload, ischaemic injury and cardiotoxicity, with clinical trials begun to explore dilated cardiomyopathy and heart failure with preserved ejection fraction.

   Phosphodiesterase 5 family → Cyclic guanosine monophosphate source_derived_draftungraded
   Experimental context and source evidence

   evidence_span

   {"source_cache": "artifacts/sildenafil-research/22798047.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "5456b43dcdb907d5a82ca9999cc94cb6c584589d0b454e1cdbf44fb3ee40941f", "start_char": 0, "end_char": 799, "text_sha256": "5456b43dcdb907d5a82ca9999cc94cb6c584589d0b454e1cdbf44fb3ee40941f"}

   experimental_model

   Review of cyclic GMP and protein kinase G signalling in cardiac stress remodelling

   exposure

   Phosphodiesterase type 5 inhibition across models of pressure and volume overload, ischaemic injury and cardiotoxicity

   limitations

   A review summarising preclinical work and stating the clinical trials as ongoing. It reports the expectation that the trial in the next record went on to test.

   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

   Animal and human

   plain_language

   In animal hearts under strain, blocking this enzyme helped, and that is what the trials set out to confirm.

   primary_references

   [sil-p22798047] Cardiac role of cyclic-GMP hydrolyzing phosphodiesterase type 5: from experimental models to clinical trials. (2012). https://pubmed.ncbi.nlm.nih.gov/22798047/ DOI: 10.1007/s11897-012-0101-0

   tissue_or_cell_type

   Myocardium

   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 600–611

   AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Review of cyclic GMP and protein kinase G signalling in cardiac stress remodelling · source_derived_draft · unverified_draft

   ### sil-preclinical-cardiac-promise Cyclic GMP and its primary signalling kinase protein kinase G play a role in counterbalancing stress remodelling in the heart, growing evidence supports a positive impact on a variety of cardiac disease conditions from suppression of cyclic GMP hydrolysis which is regulated by phosphodiesterase family members of which cyclic-GMP-selective PDE5 has been best studied, and inhibitors such as sildenafil and tadalafil ameliorate cardiac pressure and volume overload, ischaemic injury and cardiotoxicity, with clinical trials begun to explore dilated cardiomyopathy and heart failure with preserved ejection fraction. 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: In animal hearts under strain, blocking this enzyme helped, and that is what the trials set out to confirm. organism: Animal and human tissue_or_cell_type: Myocardium experimental_model: Review of cyclic GMP and protein kinase G signalling in cardiac stress remodelling limitations: A review summarising preclinical work and stating the clinical trials as ongoing. It reports the expectation that the trial in the next record went on to test. exposure: Phosphodiesterase type 5 inhibition across models of pressure and volume overload, ischaemic injury and cardiotoxicity evidence_span: {"source_cache": "artifacts/sildenafil-research/22798047.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "5456b43dcdb907d5a82ca9999cc94cb6c584589d0b454e1cdbf44fb3ee40941f", "start_char": 0, "end_char": 799, "text_sha256": "5456b43dcdb907d5a82ca9999cc94cb6c584589d0b454e1cdbf44fb3ee40941f"} [sil-p22798047] Cardiac role of cyclic-GMP hydrolyzing phosphodiesterase type 5: from experimental models to clinical trials. (2012). https://pubmed.ncbi.nlm.nih.gov/22798047/ DOI: 10.1007/s11897-012-0101-0

   Complete structured claim and evidence

3. Sildenafil inhibited PDE5 from human corpus cavernosum with a geometric mean half-maximal inhibitory concentration of 3.5 nanomolar and was approximately 240-fold more potent than zaprinast, values for inhibition of PDE1 to PDE4 were 80 to more than 8500 times greater than that for PDE5, and the value for PDE6 at 33 nanomolar was approximately 9-fold greater.

   Sildenafil → Phosphodiesterase 5 family source_derived_draftungraded
   Experimental context and source evidence

   evidence_span

   {"source_cache": "artifacts/sildenafil-research/9598563.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "860e09237bbae4ec5bb65a640186902908ccb9c6ec502b504a1ecddbb33810a2", "start_char": 0, "end_char": 1755, "text_sha256": "860e09237bbae4ec5bb65a640186902908ccb9c6ec502b504a1ecddbb33810a2"}

   experimental_model

   Isolated human corpus cavernosum strips with electrical field stimulation, and phosphodiesterase assays across families 1 to 6

   exposure

   Sildenafil against PDE1 to PDE5 prepared from human tissues and PDE6 from bovine retina, with zaprinast as comparator

   limitations

   Measures the full selectivity series in one laboratory using the same method, which is what makes the ratios comparable. The PDE6 preparation is bovine retina rather than human.

   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 and bovine enzyme

   plain_language

   It is hundreds to thousands of times more selective against most of the enzyme family, and only about nine times against the one in the retina.

   primary_references

   [sil-p9598563] Effects of sildenafil on the relaxation of human corpus cavernosum tissue in vitro and on the activities of cyclic nucleotide phosphodiesterase isozymes. (1998). https://pubmed.ncbi.nlm.nih.gov/9598563/ DOI: 10.1016/s0022-5347(01)63299-3

   tissue_or_cell_type

   Corpus cavernosum and bovine 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 132–143

   AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Isolated human corpus cavernosum strips with electrical field stimulation, and phosphodiesterase assays across families 1 to 6 · source_derived_draft · unverified_draft

   ### sil-the-selectivity-series Sildenafil inhibited PDE5 from human corpus cavernosum with a geometric mean half-maximal inhibitory concentration of 3.5 nanomolar and was approximately 240-fold more potent than zaprinast, values for inhibition of PDE1 to PDE4 were 80 to more than 8500 times greater than that for PDE5, and the value for PDE6 at 33 nanomolar was approximately 9-fold greater. 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 is hundreds to thousands of times more selective against most of the enzyme family, and only about nine times against the one in the retina. organism: Human and bovine enzyme tissue_or_cell_type: Corpus cavernosum and bovine retina experimental_model: Isolated human corpus cavernosum strips with electrical field stimulation, and phosphodiesterase assays across families 1 to 6 limitations: Measures the full selectivity series in one laboratory using the same method, which is what makes the ratios comparable. The PDE6 preparation is bovine retina rather than human. exposure: Sildenafil against PDE1 to PDE5 prepared from human tissues and PDE6 from bovine retina, with zaprinast as comparator evidence_span: {"source_cache": "artifacts/sildenafil-research/9598563.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "860e09237bbae4ec5bb65a640186902908ccb9c6ec502b504a1ecddbb33810a2", "start_char": 0, "end_char": 1755, "text_sha256": "860e09237bbae4ec5bb65a640186902908ccb9c6ec502b504a1ecddbb33810a2"} [sil-p9598563] Effects of sildenafil on the relaxation of human corpus cavernosum tissue in vitro and on the activities of cyclic nucleotide phosphodiesterase isozymes. (1998). https://pubmed.ncbi.nlm.nih.gov/9598563/ DOI: 10.1016/s0022-5347(01)63299-3

   Complete structured claim and evidence

4. In cardiac myocytes cyclic GMP is produced by soluble and particulate guanylyl cyclases, the former stimulated by nitric oxide and the latter by natriuretic peptides, and is hydrolyzed to inactive 5-GMP by cyclic GMP phosphodiesterases, cyclic GMP and protein kinase G modulate cardiac contractility, hypertrophy and remodeling and exert cardioprotection, recent studies have revealed that cyclic GMP degradation controlled by phosphodiesterases plays a critical role in the physiological action of cyclic GMP, and several clinical trials are ongoing including a large multicenter trial led by the NIH evaluating sildenafil efficacy in heart failure with preserved ejection fraction.

   Membrane-bound particulate guanylate cyclase and other non-nitric-oxide sources of cyclic GMP → Cyclic guanosine monophosphate source_derived_draftungraded
   Experimental context and source evidence

   evidence_span

   {"source_cache": "artifacts/sildenafil-research/22785374.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "14560978d3bfa37c665443c993d21b9c4a0e287c6c8c45672ee35ed55f0c6094", "start_char": 0, "end_char": 1262, "text_sha256": "14560978d3bfa37c665443c993d21b9c4a0e287c6c8c45672ee35ed55f0c6094"}

   experimental_model

   Review of cyclic GMP and protein kinase G signal regulation in the cardiac myocyte

   exposure

   Sources and degradation of cyclic GMP in the myocyte, and phosphodiesterase type 5 inhibition across cardiac pathologies

   limitations

   A review written while the definitive trial was still running, and it names that trial as the test of its own thesis.

   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

   Animal and human

   plain_language

   The messenger has a second source that answers to natriuretic peptides rather than nitric oxide.

   primary_references

   [sil-p22785374] Cyclic GMP-dependent signaling in cardiac myocytes. (2012). https://pubmed.ncbi.nlm.nih.gov/22785374/ DOI: 10.1253/circj.cj-12-0664

   tissue_or_cell_type

   Cardiac myocyte

   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 613–624

   AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Review of cyclic GMP and protein kinase G signal regulation in the cardiac myocyte · source_derived_draft · unverified_draft

   ### sil-two-sources-of-the-messenger In cardiac myocytes cyclic GMP is produced by soluble and particulate guanylyl cyclases, the former stimulated by nitric oxide and the latter by natriuretic peptides, and is hydrolyzed to inactive 5-GMP by cyclic GMP phosphodiesterases, cyclic GMP and protein kinase G modulate cardiac contractility, hypertrophy and remodeling and exert cardioprotection, recent studies have revealed that cyclic GMP degradation controlled by phosphodiesterases plays a critical role in the physiological action of cyclic GMP, and several clinical trials are ongoing including a large multicenter trial led by the NIH evaluating sildenafil efficacy in heart failure with preserved ejection fraction. 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 has a second source that answers to natriuretic peptides rather than nitric oxide. organism: Animal and human tissue_or_cell_type: Cardiac myocyte experimental_model: Review of cyclic GMP and protein kinase G signal regulation in the cardiac myocyte limitations: A review written while the definitive trial was still running, and it names that trial as the test of its own thesis. exposure: Sources and degradation of cyclic GMP in the myocyte, and phosphodiesterase type 5 inhibition across cardiac pathologies evidence_span: {"source_cache": "artifacts/sildenafil-research/22785374.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "14560978d3bfa37c665443c993d21b9c4a0e287c6c8c45672ee35ed55f0c6094", "start_char": 0, "end_char": 1262, "text_sha256": "14560978d3bfa37c665443c993d21b9c4a0e287c6c8c45672ee35ed55f0c6094"} [sil-p22785374] Cyclic GMP-dependent signaling in cardiac myocytes. (2012). https://pubmed.ncbi.nlm.nih.gov/22785374/ DOI: 10.1253/circj.cj-12-0664

   Complete structured claim and evidence

5. Sildenafil and zaprinast are both competitive inhibitors of PDE5 and double-inhibition analysis shows they interact with the catalytic site in a mutually exclusive manner, with inhibition constants of 1 nanomolar for sildenafil, 5 nanomolar for UK-122764 and 130 nanomolar for zaprinast, and the affinity of each of these inhibitors for the enzyme is much higher than that of cyclic GMP itself whose Michaelis constant is 2000 nanomolar.

   Sildenafil → The catalytic site of phosphodiesterase type 5 source_derived_draftungraded
   Experimental context and source evidence

   evidence_span

   {"source_cache": "artifacts/sildenafil-research/10385692.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "9ce2e7f3f2d22246734a6f998124d7a57cc0eded673f321bbc47586fd2ea3bcf", "start_char": 0, "end_char": 1888, "text_sha256": "9ce2e7f3f2d22246734a6f998124d7a57cc0eded673f321bbc47586fd2ea3bcf"}

   experimental_model

   Kinetic and site-directed mutagenesis analysis of inhibitor interaction with the phosphodiesterase type 5 catalytic domain

   exposure

   Sildenafil, UK-122764 and zaprinast against wild-type enzyme and 23 conserved catalytic-domain point mutants

   limitations

   Places the drug at the catalytic site by competition and by a mutant series, and gives the comparison with the natural substrate that makes the affinity meaningful. Recombinant enzyme.

   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

   Enzyme

   plain_language

   The drug holds the working part of the enzyme about two thousand times more tightly than the molecule the enzyme is meant to destroy.

   primary_references

   [sil-p10385692] Inhibition of cyclic GMP-binding cyclic GMP-specific phosphodiesterase (Type 5) by sildenafil and related compounds. (1999). https://pubmed.ncbi.nlm.nih.gov/10385692/ DOI: 10.1124/mol.56.1.124

   tissue_or_cell_type

   Recombinant phosphodiesterase type 5

   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 158–169

   AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Kinetic and site-directed mutagenesis analysis of inhibitor interaction with the phosphodiesterase type 5 catalytic domain · source_derived_draft · unverified_draft

   ### sil-two-thousand-fold-over-substrate Sildenafil and zaprinast are both competitive inhibitors of PDE5 and double-inhibition analysis shows they interact with the catalytic site in a mutually exclusive manner, with inhibition constants of 1 nanomolar for sildenafil, 5 nanomolar for UK-122764 and 130 nanomolar for zaprinast, and the affinity of each of these inhibitors for the enzyme is much higher than that of cyclic GMP itself whose Michaelis constant is 2000 nanomolar. 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 drug holds the working part of the enzyme about two thousand times more tightly than the molecule the enzyme is meant to destroy. organism: Enzyme tissue_or_cell_type: Recombinant phosphodiesterase type 5 experimental_model: Kinetic and site-directed mutagenesis analysis of inhibitor interaction with the phosphodiesterase type 5 catalytic domain limitations: Places the drug at the catalytic site by competition and by a mutant series, and gives the comparison with the natural substrate that makes the affinity meaningful. Recombinant enzyme. exposure: Sildenafil, UK-122764 and zaprinast against wild-type enzyme and 23 conserved catalytic-domain point mutants evidence_span: {"source_cache": "artifacts/sildenafil-research/10385692.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "9ce2e7f3f2d22246734a6f998124d7a57cc0eded673f321bbc47586fd2ea3bcf", "start_char": 0, "end_char": 1888, "text_sha256": "9ce2e7f3f2d22246734a6f998124d7a57cc0eded673f321bbc47586fd2ea3bcf"} [sil-p10385692] Inhibition of cyclic GMP-binding cyclic GMP-specific phosphodiesterase (Type 5) by sildenafil and related compounds. (1999). https://pubmed.ncbi.nlm.nih.gov/10385692/ DOI: 10.1124/mol.56.1.124

   Complete structured claim and evidence