Phosphodiesterase 5 family

evidence_span

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experimental_model

Immunochemical distribution of phosphodiesterase activity across human tissues with isolated organ bath studies and platelet aggregometry

exposure

Anti-PDE1 and anti-PDE5 antibodies with functional testing, and sildenafil against sodium nitroprusside on platelets

limitations

Maps where the target enzyme is and is not, which is what predicts where the drug acts. Antibody-based detection, so absence of signal is weaker evidence than presence.

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

The target enzyme is in blood vessels and not detectable in heart muscle, which is where the drug does and does not act.

primary_references

[sil-p10078537] Tissue distribution of phosphodiesterase families and the effects of sildenafil on tissue cyclic nucleotides, platelet function, and the contractile responses of trabeculae carneae and aortic rings in vitro. (1999). https://pubmed.ncbi.nlm.nih.gov/10078537/ DOI: 10.1016/s0002-9149(99)00042-9

tissue_or_cell_type

Cardiac ventricle, saphenous vein, mesenteric artery, corpus cavernosum and 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 314–325

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Immunochemical distribution of phosphodiesterase activity across human tissues with isolated organ bath studies and platelet aggregometry · source_derived_draft · unverified_draft

### sil-no-pde5-in-the-ventricle The major phosphodiesterase activity in the human cardiac ventricle was calcium and calmodulin-dependent PDE1 with no detectable level of PDE5, whereas human saphenous vein contained PDE1, PDE4 and PDE5 and human mesenteric artery contained PDE1, PDE2, PDE3, PDE4 and PDE5, and sildenafil unlike milrinone had no effect on isolated trabeculae carneae, consistent with the lack of PDE5 expression in cardiac myocytes. 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 target enzyme is in blood vessels and not detectable in heart muscle, which is where the drug does and does not act. organism: Human, rabbit and dog tissue_or_cell_type: Cardiac ventricle, saphenous vein, mesenteric artery, corpus cavernosum and platelets experimental_model: Immunochemical distribution of phosphodiesterase activity across human tissues with isolated organ bath studies and platelet aggregometry limitations: Maps where the target enzyme is and is not, which is what predicts where the drug acts. Antibody-based detection, so absence of signal is weaker evidence than presence. exposure: Anti-PDE1 and anti-PDE5 antibodies with functional testing, and sildenafil against sodium nitroprusside on platelets evidence_span: {"source_cache": "artifacts/sildenafil-research/10078537.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "dceb60af4400fe67b4ffaf73a0aadb8d2e5fad0966b3372a3e46a91c0e0ccee5", "start_char": 0, "end_char": 2610, "text_sha256": "dceb60af4400fe67b4ffaf73a0aadb8d2e5fad0966b3372a3e46a91c0e0ccee5"} [sil-p10078537] Tissue distribution of phosphodiesterase families and the effects of sildenafil on tissue cyclic nucleotides, platelet function, and the contractile responses of trabeculae carneae and aortic rings in vitro. (1999). https://pubmed.ncbi.nlm.nih.gov/10078537/ DOI: 10.1016/s0002-9149(99)00042-9

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/

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

evidence_access

Primary PubMed abstract and indexed metadata reviewed. Full-text method details not stated here remain unresolved.

experimental_model

Human corpus cavernosum tissue, as stated in a structural report

exposure

Not applicable

limitations

Stated as established background in this structural paper rather than measured in it; twelve PDE gene families exist and others are present in the same tissue.

organism

Human corpus cavernosum tissue, as stated in a structural report

plain_language

cGMP-specific PDE5 carries out the principal cGMP-hydrolysing activity in human corpus cavernosum tissue.

primary_references

Structure of the catalytic domain of human phosphodiesterase 5 with bound drug molecules. (2003). https://pubmed.ncbi.nlm.nih.gov/12955149/ DOI: 10.1038/nature01914

route

Not applicable

tissue

Cyclic nucleotide degradation

Tadalafil: PDE5 occupancy, the cGMP route and three measured endpoints (2026-09-22) · lines 46–54

Original AI-assisted curation of seven primary studies resolved by PubMed title search, with every abstract read and all DOIs cross-checked against live PubMed metadata. Two references carry an unresolvable erratum and are recorded as corrected. Study-specific doses, effect sizes and limitations retained. Not publisher full text. · supports · · source_derived_draft · unverified_draft

## pde5-hydrolyses-cgmp-in-corpus-cavernosum cGMP-specific PDE5 carries out the principal cGMP-hydrolysing activity in human corpus cavernosum tissue. Model/species: Human corpus cavernosum tissue, as stated in a structural report Tissue/system: Cyclic nucleotide degradation Exposure: Not applicable Route: Not applicable Limits: Stated as established background in this structural paper rather than measured in it; twelve PDE gene families exist and others are present in the same tissue. Primary reference: Structure of the catalytic domain of human phosphodiesterase 5 with bound drug molecules. (2003). https://pubmed.ncbi.nlm.nih.gov/12955149/ DOI: 10.1038/nature01914 Access: Primary PubMed abstract and indexed metadata reviewed. Full-text method details not stated here remain unresolved.

experimental_model

Cancer-cell experiments and mouse xenografts in the 2013 study.

limitations

Preclinical combination experiments; normal-cell selectivity in tested preparations is not universal safety.

nutrient_topic

EGCG collection; comparator and shared-pathway records retain their actual intervention. · Epigallocatechin-3-gallate (EGCG)

plain_language

An enzyme that removes cGMP can limit the response.

primary_references

67-kDa laminin receptor increases cGMP to induce cancer-selective apoptosis. · 2013 · https://pubmed.ncbi.nlm.nih.gov/23348740/ · DOI 10.1172/jci64768

EGCG: receptor signaling, metabolism, nutrient interactions and discovery questions (2026-09-18) · lines 84–90

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Cancer-cell experiments and mouse xenografts in the 2013 study. · source_derived_draft · unverified_draft

## egcg-pde5 An enzyme that removes cGMP can limit the response. Overexpressed PDE5 attenuated the cGMP-dependent anticancer signal. Model: Cancer-cell experiments and mouse xenografts in the 2013 study. Limitations: Preclinical combination experiments; normal-cell selectivity in tested preparations is not universal safety. Evidence access: primary abstract. 67-kDa laminin receptor increases cGMP to induce cancer-selective apoptosis. · 2013 · https://pubmed.ncbi.nlm.nih.gov/23348740/ · DOI 10.1172/jci64768

evidence_span

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experimental_model

Electron microscopy and single-particle image analysis of purified bovine rod phosphodiesterase 6

exposure

Solubilised rod PDE6 depleted of its gamma subunits, with immunolabelling

limitations

A structural comparison at 2.8 nanometre resolution rather than atomic detail. The comparison with PDE5 is inferred from sequence similarity and the reconstructed organisation.

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

plain_language

The retinal enzyme and the target enzyme are built to the same plan, which is why a drug for one reaches the other.

primary_references

[sil-p11453687] Molecular organization of bovine rod cGMP-phosphodiesterase 6. (2001). https://pubmed.ncbi.nlm.nih.gov/11453687/ DOI: 10.1006/jmbi.2001.4813

tissue_or_cell_type

Retinal rod outer segment

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 249–260

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Electron microscopy and single-particle image analysis of purified bovine rod phosphodiesterase 6 · source_derived_draft · unverified_draft

### sil-pde5-and-pde6-are-built-alike Image analysis of purified bovine rod phosphodiesterase 6 revealed the three-dimensional dimeric arrangement of the alpha-beta-delta complex and the internal organization of each catalytic subunit into three distinct domains corresponding to the catalytic and two GAF domains, and the three-dimensional molecular organization of human platelet phosphodiesterase type 5 appears highly homologous to that of bovine rod phosphodiesterase 6 as predicted by similarities in their primary sequences. 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 retinal enzyme and the target enzyme are built to the same plan, which is why a drug for one reaches the other. organism: Cattle tissue_or_cell_type: Retinal rod outer segment experimental_model: Electron microscopy and single-particle image analysis of purified bovine rod phosphodiesterase 6 limitations: A structural comparison at 2.8 nanometre resolution rather than atomic detail. The comparison with PDE5 is inferred from sequence similarity and the reconstructed organisation. exposure: Solubilised rod PDE6 depleted of its gamma subunits, with immunolabelling evidence_span: {"source_cache": "artifacts/sildenafil-research/11453687.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "54fdc1cf336b81568055fa21b19ad21600db5bf276dc5dc9e1dcb490cb63de30", "start_char": 0, "end_char": 1312, "text_sha256": "54fdc1cf336b81568055fa21b19ad21600db5bf276dc5dc9e1dcb490cb63de30"} [sil-p11453687] Molecular organization of bovine rod cGMP-phosphodiesterase 6. (2001). https://pubmed.ncbi.nlm.nih.gov/11453687/ DOI: 10.1006/jmbi.2001.4813

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

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

duration

Not applicable

evidence_access

Primary PubMed abstract and indexed metadata reviewed. Full-text method details not stated here remain unresolved.

experimental_model

Human PDE5 catalytic domain

exposure

Each of the three drug molecules complexed with the enzyme

limitations

The catalytic domain alone was crystallised, not the full-length regulated enzyme, so the structures do not describe the allosteric cGMP-binding GAF domains.

organism

Human PDE5 catalytic domain

plain_language

Three-dimensional structures of the catalytic domain of human PDE5, residues 537 to 860, were determined in complex with sildenafil, tadalafil and vardenafil.

primary_references

Structure of the catalytic domain of human phosphodiesterase 5 with bound drug molecules. (2003). https://pubmed.ncbi.nlm.nih.gov/12955149/ DOI: 10.1038/nature01914

route

Structural

tissue

Inhibitor binding at the catalytic site

Tadalafil: PDE5 occupancy, the cGMP route and three measured endpoints (2026-09-22) · lines 35–44

Original AI-assisted curation of seven primary studies resolved by PubMed title search, with every abstract read and all DOIs cross-checked against live PubMed metadata. Two references carry an unresolvable erratum and are recorded as corrected. Study-specific doses, effect sizes and limitations retained. Not publisher full text. · supports · · source_derived_draft · unverified_draft

## pde5-binding-site-resolved-with-tadalafil Three-dimensional structures of the catalytic domain of human PDE5, residues 537 to 860, were determined in complex with sildenafil, tadalafil and vardenafil. Model/species: Human PDE5 catalytic domain Tissue/system: Inhibitor binding at the catalytic site Exposure: Each of the three drug molecules complexed with the enzyme Route: Structural Duration: Not applicable Limits: The catalytic domain alone was crystallised, not the full-length regulated enzyme, so the structures do not describe the allosteric cGMP-binding GAF domains. Primary reference: Structure of the catalytic domain of human phosphodiesterase 5 with bound drug molecules. (2003). https://pubmed.ncbi.nlm.nih.gov/12955149/ DOI: 10.1038/nature01914 Access: Primary PubMed abstract and indexed metadata reviewed. Full-text method details not stated here remain unresolved.

duration

Not applicable

evidence_access

Primary PubMed abstract and indexed metadata reviewed. Full-text method details not stated here remain unresolved.

experimental_model

Isolated phosphodiesterase enzyme assays during medicinal-chemistry optimisation

exposure

Tadalafil, compound GF196960, the cis-(6R,12aR) enantiomer of the piperazinedione series

limitations

High diastereospecificity was observed in this series, so potency belongs to the named enantiomer and not to the racemate; selectivity was assessed against PDE1 to PDE4 and PDE6 in this report and not across all twelve families.

organism

Isolated phosphodiesterase enzyme assays during medicinal-chemistry optimisation

plain_language

Tadalafil is a highly potent PDE5 inhibitor with a half-maximal inhibitory concentration of 5 nanomolar and high selectivity for PDE5 over PDE1 to PDE4 and PDE6.

primary_references

The discovery of tadalafil: a novel and highly selective PDE5 inhibitor. 2. (2003). https://pubmed.ncbi.nlm.nih.gov/14521415/ DOI: 10.1021/jm0300577

route

In vitro

tissue

Phosphodiesterase inhibition across isoenzymes

Tadalafil: PDE5 occupancy, the cGMP route and three measured endpoints (2026-09-22) · lines 13–22

Original AI-assisted curation of seven primary studies resolved by PubMed title search, with every abstract read and all DOIs cross-checked against live PubMed metadata. Two references carry an unresolvable erratum and are recorded as corrected. Study-specific doses, effect sizes and limitations retained. Not publisher full text. · supports · · source_derived_draft · unverified_draft

## tadalafil-inhibits-pde5 Tadalafil is a highly potent PDE5 inhibitor with a half-maximal inhibitory concentration of 5 nanomolar and high selectivity for PDE5 over PDE1 to PDE4 and PDE6. Model/species: Isolated phosphodiesterase enzyme assays during medicinal-chemistry optimisation Tissue/system: Phosphodiesterase inhibition across isoenzymes Exposure: Tadalafil, compound GF196960, the cis-(6R,12aR) enantiomer of the piperazinedione series Route: In vitro Duration: Not applicable Limits: High diastereospecificity was observed in this series, so potency belongs to the named enantiomer and not to the racemate; selectivity was assessed against PDE1 to PDE4 and PDE6 in this report and not across all twelve families. Primary reference: The discovery of tadalafil: a novel and highly selective PDE5 inhibitor. 2. (2003). https://pubmed.ncbi.nlm.nih.gov/14521415/ DOI: 10.1021/jm0300577 Access: Primary PubMed abstract and indexed metadata reviewed. Full-text method details not stated here remain unresolved.

evidence_span

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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

evidence_span

{"source_cache": "artifacts/sildenafil-research/11032796.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "c3fde3e8ef99d45fbe9c59a9f4eba5a696b7e212dd2fc6d23999ce724d2996d9", "start_char": 0, "end_char": 1012, "text_sha256": "c3fde3e8ef99d45fbe9c59a9f4eba5a696b7e212dd2fc6d23999ce724d2996d9"}

experimental_model

Crystal structure of a GAF domain at 1.9 angstrom with homology modelling and mutagenesis of the phosphodiesterase type 5 domain

exposure

Cyclic GMP binding to the isolated first GAF domain of phosphodiesterase type 5

limitations

A structure of a related domain plus modelling rather than a structure of the phosphodiesterase domain itself. The binding constant is measured directly.

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

Yeast and human protein

plain_language

The regulatory half of the enzyme is itself a receptor for the messenger it destroys.

primary_references

[sil-p11032796] Structure of the GAF domain, a ubiquitous signaling motif and a new class of cyclic GMP receptor. (2000). https://pubmed.ncbi.nlm.nih.gov/11032796/ DOI: 10.1093/emboj/19.20.5288

tissue_or_cell_type

GAF domain

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 223–234

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Crystal structure of a GAF domain at 1.9 angstrom with homology modelling and mutagenesis of the phosphodiesterase type 5 domain · source_derived_draft · unverified_draft

### sil-gaf-is-a-nucleotide-receptor The isolated first GAF domain of phosphodiesterase type 5 binds cyclic GMP with a dissociation constant of 650 nanomolar, the binding site identified by homology modelling and site-directed mutagenesis consisting of conserved arginine, asparagine, lysine and aspartate residues, and the structural and binding studies together show that cyclic GMP binding GAF domains form a new class of cyclic nucleotide receptors distinct from the regulatory domains of cyclic nucleotide-regulated protein kinases and ion channels. 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 regulatory half of the enzyme is itself a receptor for the messenger it destroys. organism: Yeast and human protein tissue_or_cell_type: GAF domain experimental_model: Crystal structure of a GAF domain at 1.9 angstrom with homology modelling and mutagenesis of the phosphodiesterase type 5 domain limitations: A structure of a related domain plus modelling rather than a structure of the phosphodiesterase domain itself. The binding constant is measured directly. exposure: Cyclic GMP binding to the isolated first GAF domain of phosphodiesterase type 5 evidence_span: {"source_cache": "artifacts/sildenafil-research/11032796.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "c3fde3e8ef99d45fbe9c59a9f4eba5a696b7e212dd2fc6d23999ce724d2996d9", "start_char": 0, "end_char": 1012, "text_sha256": "c3fde3e8ef99d45fbe9c59a9f4eba5a696b7e212dd2fc6d23999ce724d2996d9"} [sil-p11032796] Structure of the GAF domain, a ubiquitous signaling motif and a new class of cyclic GMP receptor. (2000). https://pubmed.ncbi.nlm.nih.gov/11032796/ DOI: 10.1093/emboj/19.20.5288

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

evidence_span

{"source_cache": "artifacts/sildenafil-research/11351772.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "73a1ab2fa66fb9a6155ab7ccae7f405568ffdee07d4a09d61dc106e00c442711", "start_char": 0, "end_char": 1020, "text_sha256": "73a1ab2fa66fb9a6155ab7ccae7f405568ffdee07d4a09d61dc106e00c442711"}

experimental_model

Review of the coronary vascular profile assembled from haemodynamic studies and retrospective analysis of the clinical trial programme

exposure

Sildenafil at therapeutic doses in men with coronary heart disease not taking nitrates

limitations

A review rather than a new study, and the cardiac risk analyses are retrospective. It measures coronary flow in the intact circulation, where the organ bath records cannot.

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

In the living coronary circulation it did not change resting flow, though it improved the reserve the vessels could call on.

primary_references

[sil-p11351772] Phosphodiesterase 5 inhibition: effects on the coronary vasculature. (2001). https://pubmed.ncbi.nlm.nih.gov/11351772/ DOI: 10.1111/j.1742-1241.2001.tb11011.x

tissue_or_cell_type

Coronary circulation

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 379–390

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Review of the coronary vascular profile assembled from haemodynamic studies and retrospective analysis of the clinical trial programme · source_derived_draft · unverified_draft

### sil-no-change-in-coronary-flow In haemodynamic studies sildenafil produced small decreases in systemic and pulmonary blood pressure but caused no adverse cardiovascular effects in specific populations of men with coronary heart disease, and it caused no significant changes in coronary blood flow but had a positive effect on coronary flow reserve in men with severe coronary artery disease, suggesting that PDE5 may play an important role in the regulation of coronary blood flow in the healthy and diseased heart, while in retrospective analyses of extensive clinical trials treatment was not associated with any increase in cardiac risk in patients not receiving organic nitrates or nitrate donor drugs. 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 the living coronary circulation it did not change resting flow, though it improved the reserve the vessels could call on. organism: Human tissue_or_cell_type: Coronary circulation experimental_model: Review of the coronary vascular profile assembled from haemodynamic studies and retrospective analysis of the clinical trial programme limitations: A review rather than a new study, and the cardiac risk analyses are retrospective. It measures coronary flow in the intact circulation, where the organ bath records cannot. exposure: Sildenafil at therapeutic doses in men with coronary heart disease not taking nitrates evidence_span: {"source_cache": "artifacts/sildenafil-research/11351772.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "73a1ab2fa66fb9a6155ab7ccae7f405568ffdee07d4a09d61dc106e00c442711", "start_char": 0, "end_char": 1020, "text_sha256": "73a1ab2fa66fb9a6155ab7ccae7f405568ffdee07d4a09d61dc106e00c442711"} [sil-p11351772] Phosphodiesterase 5 inhibition: effects on the coronary vasculature. (2001). https://pubmed.ncbi.nlm.nih.gov/11351772/ DOI: 10.1111/j.1742-1241.2001.tb11011.x

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

evidence_span

{"source_cache": "artifacts/sildenafil-research/10703120.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "fc004205f7e036cf52e469c5f9941c4f69d216a012ccd8a588052b950c1077e6", "start_char": 0, "end_char": 2146, "text_sha256": "fc004205f7e036cf52e469c5f9941c4f69d216a012ccd8a588052b950c1077e6"}

experimental_model

Review of how the ocular safety profile was established from preclinical work through to post-marketing surveillance

exposure

Electroretinography and histology in preclinical evaluation, with extended eye examination in clinical protocols and registry surveillance

limitations

A methodological review of how the signal was tracked rather than a new measurement. It is useful because it records that the retinal effect was predicted before it was looked for.

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 animal

plain_language

The visual effect was not a surprise; the homology between the two enzymes predicted it and the trials were designed to look for it.

primary_references

[sil-p10703120] Ocular safety of Viagra, (sildenafil citrate). (1999). https://pubmed.ncbi.nlm.nih.gov/10703120/

tissue_or_cell_type

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 496–507

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Review of how the ocular safety profile was established from preclinical work through to post-marketing surveillance · source_derived_draft · unverified_draft

### sil-the-off-target-was-predicted Early in development it was noted that besides its major inhibitory effect on the intended target, the vascular-associated PDE5, the drug also exerts a lesser but definite inhibitory effect on the closely related PDE6 located in the retina, and for this reason preclinical evaluation included electroretinography plus postmortem histology and an extended eye examination was incorporated into clinical protocols, with data on the incidence, duration and type of colour vision defects observed at different doses. 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 visual effect was not a surprise; the homology between the two enzymes predicted it and the trials were designed to look for it. organism: Human and animal tissue_or_cell_type: Retina experimental_model: Review of how the ocular safety profile was established from preclinical work through to post-marketing surveillance limitations: A methodological review of how the signal was tracked rather than a new measurement. It is useful because it records that the retinal effect was predicted before it was looked for. exposure: Electroretinography and histology in preclinical evaluation, with extended eye examination in clinical protocols and registry surveillance evidence_span: {"source_cache": "artifacts/sildenafil-research/10703120.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "fc004205f7e036cf52e469c5f9941c4f69d216a012ccd8a588052b950c1077e6", "start_char": 0, "end_char": 2146, "text_sha256": "fc004205f7e036cf52e469c5f9941c4f69d216a012ccd8a588052b950c1077e6"} [sil-p10703120] Ocular safety of Viagra, (sildenafil citrate). (1999). https://pubmed.ncbi.nlm.nih.gov/10703120/

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

duration

12 weeks

evidence_access

Primary PubMed abstract and indexed metadata reviewed. Full-text method details not stated here remain unresolved.

experimental_model

1500 men pooled from four international randomised placebo-controlled studies

exposure

Tadalafil 5 mg once daily against placebo

limitations

A pooled analysis rather than a single trial. Improvements were significant regardless of baseline symptom severity, age, recent alpha-blocker or PDE5 inhibitor use, total testosterone or predicted prostate volume, so no subgroup was identified in which the effect was absent, and the mechanism in this tissue is not established by the symptom score. PubMed records an erratum for this paper without a resolvable identifier, and the abstract itself carries an inline corrected marker, so it is not known whether the erratum altered these figures.

organism

1500 men pooled from four international randomised placebo-controlled studies

plain_language

Tadalafil 5 mg once daily improved the total International Prostate Symptom Score by a mean difference of 2.3 points against placebo in men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia.

primary_references

Efficacy and safety of tadalafil 5 mg once daily for lower urinary tract symptoms suggestive of benign prostatic hyperplasia. (2013). https://pubmed.ncbi.nlm.nih.gov/23876588/ DOI: 10.1016/j.urology.2013.05.005

route

Oral

tissue

Lower urinary tract symptoms

Tadalafil: PDE5 occupancy, the cGMP route and three measured endpoints (2026-09-22) · lines 111–120

Original AI-assisted curation of seven primary studies resolved by PubMed title search, with every abstract read and all DOIs cross-checked against live PubMed metadata. Two references carry an unresolvable erratum and are recorded as corrected. Study-specific doses, effect sizes and limitations retained. Not publisher full text. · supports · · source_derived_draft · unverified_draft

## tadalafil-lowers-prostate-symptom-score Tadalafil 5 mg once daily improved the total International Prostate Symptom Score by a mean difference of 2.3 points against placebo in men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia. Model/species: 1500 men pooled from four international randomised placebo-controlled studies Tissue/system: Lower urinary tract symptoms Exposure: Tadalafil 5 mg once daily against placebo Route: Oral Duration: 12 weeks Limits: A pooled analysis rather than a single trial. Improvements were significant regardless of baseline symptom severity, age, recent alpha-blocker or PDE5 inhibitor use, total testosterone or predicted prostate volume, so no subgroup was identified in which the effect was absent, and the mechanism in this tissue is not established by the symptom score. PubMed records an erratum for this paper without a resolvable identifier, and the abstract itself carries an inline corrected marker, so it is not known whether the erratum altered these figures. Primary reference: Efficacy and safety of tadalafil 5 mg once daily for lower urinary tract symptoms suggestive of benign prostatic hyperplasia. (2013). https://pubmed.ncbi.nlm.nih.gov/23876588/ DOI: 10.1016/j.urology.2013.05.005 Access: Primary PubMed abstract and indexed metadata reviewed. Full-text method details not stated here remain unresolved.

duration

Not applicable

evidence_access

Primary PubMed abstract and indexed metadata reviewed. Full-text method details not stated here remain unresolved.

experimental_model

Isolated phosphodiesterase enzyme assays

exposure

Tadalafil compared with sildenafil

limitations

A ratio measured in enzyme assays; PDE6 is the retinal phototransduction phosphodiesterase, and this comparison does not by itself establish a difference in visual effects in people.

organism

Isolated phosphodiesterase enzyme assays

plain_language

Tadalafil showed 85-fold greater selectivity against PDE6 than sildenafil.

primary_references

The discovery of tadalafil: a novel and highly selective PDE5 inhibitor. 2. (2003). https://pubmed.ncbi.nlm.nih.gov/14521415/ DOI: 10.1021/jm0300577

route

In vitro

tissue

Selectivity ratio between PDE5 and PDE6

Tadalafil: PDE5 occupancy, the cGMP route and three measured endpoints (2026-09-22) · lines 24–33

Original AI-assisted curation of seven primary studies resolved by PubMed title search, with every abstract read and all DOIs cross-checked against live PubMed metadata. Two references carry an unresolvable erratum and are recorded as corrected. Study-specific doses, effect sizes and limitations retained. Not publisher full text. · supports · · source_derived_draft · unverified_draft

## tadalafil-pde6-selectivity-versus-sildenafil Tadalafil showed 85-fold greater selectivity against PDE6 than sildenafil. Model/species: Isolated phosphodiesterase enzyme assays Tissue/system: Selectivity ratio between PDE5 and PDE6 Exposure: Tadalafil compared with sildenafil Route: In vitro Duration: Not applicable Limits: A ratio measured in enzyme assays; PDE6 is the retinal phototransduction phosphodiesterase, and this comparison does not by itself establish a difference in visual effects in people. Primary reference: The discovery of tadalafil: a novel and highly selective PDE5 inhibitor. 2. (2003). https://pubmed.ncbi.nlm.nih.gov/14521415/ DOI: 10.1021/jm0300577 Access: Primary PubMed abstract and indexed metadata reviewed. Full-text method details not stated here remain unresolved.

experimental_model

Cancer-cell experiments and mouse xenografts in the 2013 study.

limitations

Preclinical combination experiments; normal-cell selectivity in tested preparations is not universal safety.

nutrient_topic

EGCG collection; comparator and shared-pathway records retain their actual intervention. · Epigallocatechin-3-gallate (EGCG)

plain_language

Blocking the opposing enzyme strengthened the response in these models.

primary_references

67-kDa laminin receptor increases cGMP to induce cancer-selective apoptosis. · 2013 · https://pubmed.ncbi.nlm.nih.gov/23348740/ · DOI 10.1172/jci64768

EGCG: receptor signaling, metabolism, nutrient interactions and discovery questions (2026-09-18) · lines 92–98

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Cancer-cell experiments and mouse xenografts in the 2013 study. · source_derived_draft · unverified_draft

## egcg-vardenafil Blocking the opposing enzyme strengthened the response in these models. PDE5 inhibition with vardenafil potentiated EGCG-dependent apoptosis and prolonged survival in a mouse xenograft experiment. Model: Cancer-cell experiments and mouse xenografts in the 2013 study. Limitations: Preclinical combination experiments; normal-cell selectivity in tested preparations is not universal safety. Evidence access: primary abstract. 67-kDa laminin receptor increases cGMP to induce cancer-selective apoptosis. · 2013 · https://pubmed.ncbi.nlm.nih.gov/23348740/ · DOI 10.1172/jci64768