Cyclic guanosine monophosphate

experimental_model

Inside-out patch; cGMP EC50 about 30 micromolar

limitations

The historical experiment measured conductance before modern channel-subunit assignment.

nutrient_topic

Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A

organism

Rana temporaria

plain_language

cGMP directly keeps the rod cation channel open.

primary_references

[fesenko-1985] Induction by cyclic GMP of cationic conductance in plasma membrane of retinal rod outer segment (1985). https://pubmed.ncbi.nlm.nih.gov/2578616/ DOI: 10.1038/313310a0

tissue_or_cell_type

Rod outer-segment plasma membrane

Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 938–947

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Inside-out patch; cGMP EC50 about 30 micromolar · source_derived_draft · unverified_draft

### a-vision-cgmp-channel Cytoplasmic-side cGMP reversibly increased cation conductance in excised rod outer-segment patches without nucleoside triphosphates. Condition category: normal nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: cGMP directly keeps the rod cation channel open. organism: Rana temporaria tissue_or_cell_type: Rod outer-segment plasma membrane experimental_model: Inside-out patch; cGMP EC50 about 30 micromolar limitations: The historical experiment measured conductance before modern channel-subunit assignment. [fesenko-1985] Induction by cyclic GMP of cationic conductance in plasma membrane of retinal rod outer segment (1985). https://pubmed.ncbi.nlm.nih.gov/2578616/ DOI: 10.1038/313310a0

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

cGMP connected the receptor to a lipid-signaling enzyme.

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 68–74

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-pkcd cGMP connected the receptor to a lipid-signaling enzyme. The cGMP-dependent death pathway engaged PKC delta and acid sphingomyelinase. 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

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

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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

availability_state

biomarker_context Imported condition classification; unverified.

evidence_span

{"source_cache": "artifacts/sildenafil-research/10078541.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "e65228d2afaad9ce38dccf42c7279ec6b562746aa27b121bf5e5782f36cbe593", "start_char": 0, "end_char": 2772, "text_sha256": "e65228d2afaad9ce38dccf42c7279ec6b562746aa27b121bf5e5782f36cbe593"}

experimental_model

Review of the cardiovascular profile from the clinical development programme and post-marketing surveillance

exposure

Sildenafil alone and with antihypertensive classes, across clinical trials and spontaneous reports

limitations

A manufacturer-authored review of the development programme rather than an independent analysis, and the post-marketing comparisons are retrospective.

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

Both act on the same pathway at different points, which is why together they multiply rather than add.

primary_references

[sil-p10078541] Overall cardiovascular profile of sildenafil citrate. (1999). https://pubmed.ncbi.nlm.nih.gov/10078541/ DOI: 10.1016/s0002-9149(99)00046-6

tissue_or_cell_type

Cardiovascular system

trigger_kind

biomarker_context Imported condition classification; unverified.

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 431–442

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Review of the cardiovascular profile from the clinical development programme and post-marketing surveillance · source_derived_draft · unverified_draft

### sil-two-points-on-one-pathway Sildenafil alone can cause mean peak reductions in systolic and diastolic blood pressure of 10 and 7 millimetres of mercury that are not dose related while heart rate is unchanged, and sildenafil and nitrates both increase cyclic GMP levels in the systemic circulation but at different points along the nitric oxide to cyclic GMP pathway, so the combination is contraindicated because they synergistically potentiate vasodilation; retrospective analysis of concomitant antihypertensive medications did not indicate an increase in adverse events, and concurrent renal or hepatic impairment or CYP3A4 inhibitors could increase systemic exposure. Condition category: biomarker_context 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: Both act on the same pathway at different points, which is why together they multiply rather than add. organism: Human tissue_or_cell_type: Cardiovascular system experimental_model: Review of the cardiovascular profile from the clinical development programme and post-marketing surveillance limitations: A manufacturer-authored review of the development programme rather than an independent analysis, and the post-marketing comparisons are retrospective. exposure: Sildenafil alone and with antihypertensive classes, across clinical trials and spontaneous reports evidence_span: {"source_cache": "artifacts/sildenafil-research/10078541.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "e65228d2afaad9ce38dccf42c7279ec6b562746aa27b121bf5e5782f36cbe593", "start_char": 0, "end_char": 2772, "text_sha256": "e65228d2afaad9ce38dccf42c7279ec6b562746aa27b121bf5e5782f36cbe593"} [sil-p10078541] Overall cardiovascular profile of sildenafil citrate. (1999). https://pubmed.ncbi.nlm.nih.gov/10078541/ DOI: 10.1016/s0002-9149(99)00046-6

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

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.

evidence_span

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experimental_model

Recombinant heterodimer purification and enzyme kinetics

exposure

NO donor and YC-1 activation; GTP, cGMP and pyrophosphate kinetics

limitations

Purified-enzyme study; not a citrulline supplementation trial.

nutrient_topic

Citrulline research collection; topical membership is not evidence of a direct dietary effect. · L-Citrulline

organism

Human alpha1-beta1 sGC expressed in insect cells

plain_language

The NO receptor makes a second messenger, cGMP, linking the initial signal to downstream responses.

primary_references

[citrulline-p10995472] Human recombinant soluble guanylyl cyclase: expression, purification, and regulation. (2000). https://pubmed.ncbi.nlm.nih.gov/10995472/ DOI: 10.1073/pnas.190333697

tissue_or_cell_type

GTP conversion, heme and product inhibition

Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 489–500

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant heterodimer purification and enzyme kinetics · source_derived_draft · unverified_draft

### citrulline-sgc-cgmp Recombinant human soluble guanylate cyclase converted GTP to cGMP and pyrophosphate; both products inhibited enzyme activity in the kinetic assays. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: The NO receptor makes a second messenger, cGMP, linking the initial signal to downstream responses. organism: Human alpha1-beta1 sGC expressed in insect cells tissue_or_cell_type: GTP conversion, heme and product inhibition experimental_model: Recombinant heterodimer purification and enzyme kinetics limitations: Purified-enzyme study; not a citrulline supplementation trial. exposure: NO donor and YC-1 activation; GTP, cGMP and pyrophosphate kinetics evidence_span: {"source_cache": "artifacts/citrulline-research/10995472.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "c117699ec7c07cc54d779cc0e8274c07555b0ec93498daa8a484652edc219244", "start_char": 0, "end_char": 1300, "text_sha256": "c117699ec7c07cc54d779cc0e8274c07555b0ec93498daa8a484652edc219244"} [citrulline-p10995472] Human recombinant soluble guanylyl cyclase: expression, purification, and regulation. (2000). https://pubmed.ncbi.nlm.nih.gov/10995472/ DOI: 10.1073/pnas.190333697

experimental_model

Biochemical phosphodiesterase assay

limitations

The channel step was tested in a separate experiment.

nutrient_topic

Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A

organism

Bos taurus

plain_language

cGMP destruction passes the light signal toward channel closure.

primary_references

[fung-1981] Flow of information in the light-triggered cyclic nucleotide cascade of vision (1981). https://pubmed.ncbi.nlm.nih.gov/6264430/ DOI: 10.1073/pnas.78.1.152

tissue_or_cell_type

Rod outer-segment proteins

Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 927–936

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Biochemical phosphodiesterase assay · source_derived_draft · unverified_draft

### a-vision-pde6-cgmp Activated rod phosphodiesterase hydrolyzed cyclic GMP in the phototransduction reconstitution. Condition category: normal nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: cGMP destruction passes the light signal toward channel closure. organism: Bos taurus tissue_or_cell_type: Rod outer-segment proteins experimental_model: Biochemical phosphodiesterase assay limitations: The channel step was tested in a separate experiment. [fung-1981] Flow of information in the light-triggered cyclic nucleotide cascade of vision (1981). https://pubmed.ncbi.nlm.nih.gov/6264430/ DOI: 10.1073/pnas.78.1.152

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

The receptor signal passed through cGMP.

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 60–66

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-cgmp The receptor signal passed through cGMP. EGCG activation of 67LR increased cGMP, a rate-limiting signal for cell death in the model. 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

Site-directed mutagenesis of the two tandem allosteric cyclic GMP binding sites of phosphodiesterase type 5

exposure

D289A, D478A and D289A/D478A binding-site mutants, with phosphorylation by the catalytic subunit of cyclic AMP-dependent protein kinase

limitations

Separates what the allosteric sites do from what the catalytic site does, using mutants that lose binding at one site, the other, or both.

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 second pair of binding sites does not change how fast the enzyme works; it decides when the enzyme gets switched up.

primary_references

[sil-p9445376] Binding of cGMP to both allosteric sites of cGMP-binding cGMP-specific phosphodiesterase (PDE5) is required for its phosphorylation. (1998). https://pubmed.ncbi.nlm.nih.gov/9445376/ DOI: 10.1042/bj3290505

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 184–195

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Site-directed mutagenesis of the two tandem allosteric cyclic GMP binding sites of phosphodiesterase type 5 · source_derived_draft · unverified_draft

### sil-allosteric-sites-gate-phosphorylation Mutations affecting cyclic GMP binding to either one or both allosteric sites of phosphodiesterase type 5 do not influence cyclic GMP hydrolysis at the catalytic site under the conditions used, but the mutants defective in binding at either site require much higher cyclic GMP concentrations for allosteric stimulation of phosphorylation, while a mutant with higher binding affinity is phosphorylated at lower cyclic GMP concentrations, so binding to the allosteric sites does not directly affect catalysis but regulates phosphorylation of the enzyme. 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 second pair of binding sites does not change how fast the enzyme works; it decides when the enzyme gets switched up. organism: Enzyme tissue_or_cell_type: Recombinant phosphodiesterase type 5 experimental_model: Site-directed mutagenesis of the two tandem allosteric cyclic GMP binding sites of phosphodiesterase type 5 limitations: Separates what the allosteric sites do from what the catalytic site does, using mutants that lose binding at one site, the other, or both. exposure: D289A, D478A and D289A/D478A binding-site mutants, with phosphorylation by the catalytic subunit of cyclic AMP-dependent protein kinase evidence_span: {"source_cache": "artifacts/sildenafil-research/9445376.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "f59d258bd35b229b3455ab2d15e1d21fbe5a475a1b936ecd423eb49c9a9aea29", "start_char": 0, "end_char": 1541, "text_sha256": "f59d258bd35b229b3455ab2d15e1d21fbe5a475a1b936ecd423eb49c9a9aea29"} [sil-p9445376] Binding of cGMP to both allosteric sites of cGMP-binding cGMP-specific phosphodiesterase (PDE5) is required for its phosphorylation. (1998). https://pubmed.ncbi.nlm.nih.gov/9445376/ DOI: 10.1042/bj3290505

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 triples a relaxation the nerves were already producing; it does not produce one of its own.

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 145–156

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-amplifies-nitrergic-relaxation Sildenafil at 0.001 to 1 micromolar enhanced the electrical-field-stimulation-induced, nitric-oxide-dependent relaxation of human corpus cavernosum in a concentration-dependent manner to a maximum of three times the pretreatment level at 1 micromolar, supporting the proposal that the drug acts by potentiating the nitric-oxide-stimulated cyclic GMP signal mediating relaxation of cavernosal smooth muscle during sexual stimulation. 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 triples a relaxation the nerves were already producing; it does not produce one of its own. 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

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

evidence_span

{"source_cache": "artifacts/sildenafil-research/12021227.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "69f5687bcf1bb0fcf9d96eb7fe2f756ccfe3bbdd76af85560110b985245947e0", "start_char": 0, "end_char": 1828, "text_sha256": "69f5687bcf1bb0fcf9d96eb7fe2f756ccfe3bbdd76af85560110b985245947e0"}

experimental_model

Acute haemodynamic study in thirteen consecutive patients referred for transplantation assessment or therapy guidance

exposure

Inhaled nitric oxide at 80 parts per million, oral sildenafil 75 milligrams, and the combination, with serum cyclic GMP measured

limitations

Compares the drug directly against the reference selective pulmonary vasodilator in the same patients and measures the messenger. Thirteen patients and a single dose.

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

An oral tablet matched inhaled nitric oxide as a selective lung vasodilator and, unlike it, raised cardiac output.

primary_references

[sil-p12021227] Oral sildenafil is an effective and specific pulmonary vasodilator in patients with pulmonary arterial hypertension: comparison with inhaled nitric oxide. (2002). https://pubmed.ncbi.nlm.nih.gov/12021227/ DOI: 10.1161/01.cir.0000016641.12984.dc

tissue_or_cell_type

Pulmonary 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 535–546

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Acute haemodynamic study in thirteen consecutive patients referred for transplantation assessment or therapy guidance · source_derived_draft · unverified_draft

### sil-as-selective-as-inhaled-no In thirteen patients with severe pulmonary hypertension the decrease in pulmonary vascular resistance was similar with inhaled nitric oxide at 19% and sildenafil at 27% while the combination was more effective than inhaled nitric oxide alone at 32%, sildenafil and the combination increased cardiac index by 17% whereas inhaled nitric oxide did not, inhaled nitric oxide increased whereas sildenafil tended to decrease pulmonary capillary wedge pressure, systemic arterial pressure was similar among groups and did not decrease, and cyclic GMP rose similarly with each agent while the combination raised it synergistically. 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: An oral tablet matched inhaled nitric oxide as a selective lung vasodilator and, unlike it, raised cardiac output. organism: Human tissue_or_cell_type: Pulmonary circulation experimental_model: Acute haemodynamic study in thirteen consecutive patients referred for transplantation assessment or therapy guidance limitations: Compares the drug directly against the reference selective pulmonary vasodilator in the same patients and measures the messenger. Thirteen patients and a single dose. exposure: Inhaled nitric oxide at 80 parts per million, oral sildenafil 75 milligrams, and the combination, with serum cyclic GMP measured evidence_span: {"source_cache": "artifacts/sildenafil-research/12021227.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "69f5687bcf1bb0fcf9d96eb7fe2f756ccfe3bbdd76af85560110b985245947e0", "start_char": 0, "end_char": 1828, "text_sha256": "69f5687bcf1bb0fcf9d96eb7fe2f756ccfe3bbdd76af85560110b985245947e0"} [sil-p12021227] Oral sildenafil is an effective and specific pulmonary vasodilator in patients with pulmonary arterial hypertension: comparison with inhaled nitric oxide. (2002). https://pubmed.ncbi.nlm.nih.gov/12021227/ DOI: 10.1161/01.cir.0000016641.12984.dc

evidence_span

{"source_cache": "artifacts/sildenafil-research/10654914.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "95ba66c3ea65d0610adf58e7ab0bca314da8353ecac3f86272c780678929d292", "start_char": 0, "end_char": 1867, "text_sha256": "95ba66c3ea65d0610adf58e7ab0bca314da8353ecac3f86272c780678929d292"}

experimental_model

Radioimmunoassay of cyclic nucleotide accumulation in isolated human corpus cavernosum and cardiac muscle

exposure

Sildenafil from 0.01 to 1 micromolar against sodium nitroprusside, forskolin and milrinone as reference compounds

limitations

Measures both cyclic nucleotides in human tissue with reference compounds for each pathway, and reports an effect on the nucleotide the drug is not supposed to touch. It is an isolated tissue study without added nitric oxide drive.

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 this tissue the drug barely moved the messenger it targets and raised the other one instead.

primary_references

[sil-p10654914] Effects of sildenafil on cAMP and cGMP levels in isolated human cavernous and cardiac tissue. (2000). https://pubmed.ncbi.nlm.nih.gov/10654914/ DOI: 10.1016/s0090-4295(99)00371-4

tissue_or_cell_type

Corpus cavernosum and cardiac muscle

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 392–403

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Radioimmunoassay of cyclic nucleotide accumulation in isolated human corpus cavernosum and cardiac muscle · source_derived_draft · unverified_draft

### sil-cyclic-amp-rose-instead In the concentration range 0.01 to 1 micromolar there was only a minor effect of sildenafil on cyclic GMP levels in isolated human cavernous and cardiac tissues, whereas sildenafil significantly increased cyclic AMP in both at physiologic and supraphysiologic concentrations, more pronounced in cavernous than cardiac tissue, and in the range 0.1 to 1.0 micromolar the effect on cyclic AMP in cardiac samples was almost equivalent to that of milrinone, which the authors offer as a potential mechanism for reported cardiovascular effects and as evidence of cross-talk between the two signalling pathways. 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 this tissue the drug barely moved the messenger it targets and raised the other one instead. organism: Human tissue_or_cell_type: Corpus cavernosum and cardiac muscle experimental_model: Radioimmunoassay of cyclic nucleotide accumulation in isolated human corpus cavernosum and cardiac muscle limitations: Measures both cyclic nucleotides in human tissue with reference compounds for each pathway, and reports an effect on the nucleotide the drug is not supposed to touch. It is an isolated tissue study without added nitric oxide drive. exposure: Sildenafil from 0.01 to 1 micromolar against sodium nitroprusside, forskolin and milrinone as reference compounds evidence_span: {"source_cache": "artifacts/sildenafil-research/10654914.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "95ba66c3ea65d0610adf58e7ab0bca314da8353ecac3f86272c780678929d292", "start_char": 0, "end_char": 1867, "text_sha256": "95ba66c3ea65d0610adf58e7ab0bca314da8353ecac3f86272c780678929d292"} [sil-p10654914] Effects of sildenafil on cAMP and cGMP levels in isolated human cavernous and cardiac tissue. (2000). https://pubmed.ncbi.nlm.nih.gov/10654914/ DOI: 10.1016/s0090-4295(99)00371-4

availability_state

biomarker_context Imported condition classification; unverified.

evidence_span

{"source_cache": "artifacts/sildenafil-research/10078539.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "469d3f90cc5be3f1c0ef247d099fa70d81aa953b8a6b33334abc38d34f346654", "start_char": 0, "end_char": 3999, "text_sha256": "469d3f90cc5be3f1c0ef247d099fa70d81aa953b8a6b33334abc38d34f346654"}

experimental_model

Double-blind placebo-controlled crossover studies of nitrate and calcium antagonist coadministration in healthy men and men with hypertension

exposure

Sildenafil 25 milligrams three times daily with stepwise intravenous and sublingual glyceryl trinitrate, and a single 100 milligram dose with amlodipine

limitations

The design that establishes the contraindication, and the amlodipine arm is the control that shows it is specific to the shared pathway rather than additive antihypertensive 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

On this drug a standard nitrate tablet dropped blood pressure four times as far.

primary_references

[sil-p10078539] Sildenafil citrate and blood-pressure-lowering drugs: results of drug interaction studies with an organic nitrate and a calcium antagonist. (1999). https://pubmed.ncbi.nlm.nih.gov/10078539/ DOI: 10.1016/s0002-9149(99)00044-2

tissue_or_cell_type

Systemic circulation

trigger_kind

biomarker_context Imported condition classification; unverified.

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 405–416

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Double-blind placebo-controlled crossover studies of nitrate and calcium antagonist coadministration in healthy men and men with hypertension · source_derived_draft · unverified_draft

### sil-nitrate-potentiation-fourfold During treatment with sildenafil 25 milligrams three times daily subjects were significantly less tolerant of intravenously administered glyceryl trinitrate than during placebo based on the occurrence of a greater than 25 millimetre fall in blood pressure or symptomatic hypotension, and when a 500 microgram sublingual glyceryl trinitrate tablet was administered a fourfold greater decrease in systolic blood pressure was observed during the sildenafil period than during placebo, with negligible changes in heart rate, so that administration to patients using organic nitrates in any form is contraindicated. Condition category: biomarker_context 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: On this drug a standard nitrate tablet dropped blood pressure four times as far. organism: Human tissue_or_cell_type: Systemic circulation experimental_model: Double-blind placebo-controlled crossover studies of nitrate and calcium antagonist coadministration in healthy men and men with hypertension limitations: The design that establishes the contraindication, and the amlodipine arm is the control that shows it is specific to the shared pathway rather than additive antihypertensive effect. exposure: Sildenafil 25 milligrams three times daily with stepwise intravenous and sublingual glyceryl trinitrate, and a single 100 milligram dose with amlodipine evidence_span: {"source_cache": "artifacts/sildenafil-research/10078539.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "469d3f90cc5be3f1c0ef247d099fa70d81aa953b8a6b33334abc38d34f346654", "start_char": 0, "end_char": 3999, "text_sha256": "469d3f90cc5be3f1c0ef247d099fa70d81aa953b8a6b33334abc38d34f346654"} [sil-p10078539] Sildenafil citrate and blood-pressure-lowering drugs: results of drug interaction studies with an organic nitrate and a calcium antagonist. (1999). https://pubmed.ncbi.nlm.nih.gov/10078539/ DOI: 10.1016/s0002-9149(99)00044-2

availability_state

biomarker_context Imported condition classification; unverified.

evidence_span

{"source_cache": "artifacts/sildenafil-research/10629850.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "af056c516b44e35eac7b0511ba3a8403ed84c347af6094ebc153f68c8ee7db92", "start_char": 0, "end_char": 2057, "text_sha256": "af056c516b44e35eac7b0511ba3a8403ed84c347af6094ebc153f68c8ee7db92"}

experimental_model

Enzyme selectivity panel with isolated tissue, anaesthetised dog haemodynamics and isolated retina

exposure

Sildenafil with and without nitric oxide drive, and against glyceryl trinitrate, sodium nitroprusside and milrinone

limitations

The single most complete pharmacological characterisation here, covering the target, the absence of effect without upstream drive, the nitrate potentiation, the absence of an inotropic effect, and the retinal effect in one series.

nutrient_topic

Sildenafil research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from its N-desmethyl metabolite and its target enzyme from the homologous retinal PDE6. · Sildenafil

organism

Human, rabbit and dog

plain_language

With no signal present the drug does nothing; its entire action is to keep an existing signal from being cleared.

primary_references

[sil-p10629850] The pharmacology of sildenafil, a novel and selective inhibitor of phosphodiesterase (PDE) type 5. (1999). https://pubmed.ncbi.nlm.nih.gov/10629850/ DOI: 10.1254/fpj.114.supplement_22

tissue_or_cell_type

Corpus cavernosum, aorta, cardiac trabeculae and retina

trigger_kind

biomarker_context Imported condition classification; unverified.

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 262–273

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Enzyme selectivity panel with isolated tissue, anaesthetised dog haemodynamics and isolated retina · source_derived_draft · unverified_draft

### sil-no-effect-without-nitric-oxide Sildenafil is a potent competitive inhibitor of PDE5 with a half-maximal inhibitory concentration of 3.5 nanomolar, selective over PDE1 to PDE4 by 80 to 19,000-fold and over retinal PDE6 by 10-fold, it enhanced cyclic GMP accumulation driven with sodium nitroprusside in rabbit corpus cavernosum without affecting cyclic AMP, and in the absence of nitric oxide drive it had no functional effect on human and rabbit isolated corpus cavernosum but potently potentiated the relaxant effects of nitric oxide on these tissues. Condition category: biomarker_context 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: With no signal present the drug does nothing; its entire action is to keep an existing signal from being cleared. organism: Human, rabbit and dog tissue_or_cell_type: Corpus cavernosum, aorta, cardiac trabeculae and retina experimental_model: Enzyme selectivity panel with isolated tissue, anaesthetised dog haemodynamics and isolated retina limitations: The single most complete pharmacological characterisation here, covering the target, the absence of effect without upstream drive, the nitrate potentiation, the absence of an inotropic effect, and the retinal effect in one series. exposure: Sildenafil with and without nitric oxide drive, and against glyceryl trinitrate, sodium nitroprusside and milrinone evidence_span: {"source_cache": "artifacts/sildenafil-research/10629850.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "af056c516b44e35eac7b0511ba3a8403ed84c347af6094ebc153f68c8ee7db92", "start_char": 0, "end_char": 2057, "text_sha256": "af056c516b44e35eac7b0511ba3a8403ed84c347af6094ebc153f68c8ee7db92"} [sil-p10629850] The pharmacology of sildenafil, a novel and selective inhibitor of phosphodiesterase (PDE) type 5. (1999). https://pubmed.ncbi.nlm.nih.gov/10629850/ DOI: 10.1254/fpj.114.supplement_22

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/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/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"}

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

Platelets carry the same enzyme, and again the drug does nothing to them until a nitric oxide donor is present.

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 327–338

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-platelets-need-a-donor-too Human platelets were found to contain PDE5 which was inhibited by sildenafil with a half-maximal inhibitory concentration of 6.3 nanomolar consistent with the value in corpus cavernosum, sildenafil alone had no direct effect on platelet function but it potentiated the in vitro antiaggregatory activity of sodium nitroprusside on rabbit and human platelets, and in phenylephrine-contracted rabbit aortic rings it enhanced glyceryl trinitrate relaxation. 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: Platelets carry the same enzyme, and again the drug does nothing to them until a nitric oxide donor is present. 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/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 residues it grips are the same ones every enzyme in the family has, so what makes it selective is something else.

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 171–182

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-selectivity-is-not-in-the-conserved-residues After site-directed mutagenesis of each of 23 conserved amino acid residues in the catalytic domain, the pattern of changes in inhibitory concentration for sildenafil was most similar to that found for the affinity of cyclic GMP itself, implying similar interactions with the catalytic domain, and residues such as Tyr602, His607, His643 and Asp754 may form important interactions for sildenafil, but because these amino acids are conserved in all mammalian phosphodiesterases the selectivity and potency of the drug is likely to be provided by a nonconserved residue or residues; sildenafil also stimulates cyclic GMP binding to the allosteric sites by interacting at the catalytic site without competing for the allosteric sites themselves. 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 residues it grips are the same ones every enzyme in the family has, so what makes it selective is something else. 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

evidence_span

{"source_cache": "artifacts/sildenafil-research/10541153.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "8c5d3c6e9d606690e6cc997086ded515a4e9f785561a7fc58fdbfb75b3f0a79a", "start_char": 0, "end_char": 1024, "text_sha256": "8c5d3c6e9d606690e6cc997086ded515a4e9f785561a7fc58fdbfb75b3f0a79a"}

experimental_model

Review of the ophthalmic profile shortly after marketing approval

exposure

Reported visual effects at therapeutic doses

limitations

A short review written in the first year of marketing. It records explicitly that long-term electroretinographic studies had not been performed, which is the limitation that matters for 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 colour disturbance some people notice is the same drug reaching the retinal version of the enzyme.

primary_references

[sil-p10541153] Sildenafil (Viagra) and ophthalmology. (1999). https://pubmed.ncbi.nlm.nih.gov/10541153/ DOI: 10.1016/s0039-6257(99)00079-x

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 483–494

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Review of the ophthalmic profile shortly after marketing approval · source_derived_draft · unverified_draft

### sil-transient-visual-disturbance Sildenafil has a mild inhibitory effect on PDE6, which controls the level of cyclic guanosine monophosphate in the retina, and it may cause a perception of bluish haze or increased light sensitivity in some patients, with long-term retinal damage not reported although long-term electroretinographic studies have not been performed; the drug causes a mild lowering of blood pressure and is contraindicated in patients taking any form of nitrate medication. 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 colour disturbance some people notice is the same drug reaching the retinal version of the enzyme. organism: Human tissue_or_cell_type: Retina experimental_model: Review of the ophthalmic profile shortly after marketing approval limitations: A short review written in the first year of marketing. It records explicitly that long-term electroretinographic studies had not been performed, which is the limitation that matters for the claim. exposure: Reported visual effects at therapeutic doses evidence_span: {"source_cache": "artifacts/sildenafil-research/10541153.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "8c5d3c6e9d606690e6cc997086ded515a4e9f785561a7fc58fdbfb75b3f0a79a", "start_char": 0, "end_char": 1024, "text_sha256": "8c5d3c6e9d606690e6cc997086ded515a4e9f785561a7fc58fdbfb75b3f0a79a"} [sil-p10541153] Sildenafil (Viagra) and ophthalmology. (1999). https://pubmed.ncbi.nlm.nih.gov/10541153/ DOI: 10.1016/s0039-6257(99)00079-x

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

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_span

{"source_cache": "artifacts/sildenafil-research/11468204.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "41d880663288811422c4400d86de1eedd4d5b254d8bb3a59a8fbff01dedbcb24", "start_char": 0, "end_char": 1820, "text_sha256": "41d880663288811422c4400d86de1eedd4d5b254d8bb3a59a8fbff01dedbcb24"}

experimental_model

Randomised double-blind hypoxic challenge in ten volunteers with right heart catheterisation, plus isolated perfused lung and chronic hypoxia in wild-type and endothelial nitric oxide synthase deficient mice

exposure

Sildenafil 100 milligrams orally before 11 percent oxygen for 30 minutes, and 25 milligrams per kilogram daily through three weeks of 10 percent oxygen in mice

limitations

The knockout arm is what makes this decisive about the source of cyclic GMP, and the human arm measures pressure invasively. Ten volunteers, and the mouse exposure is far longer than the human one.

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

It still works when the main source of the upstream signal has been deleted, so something else is supplying the messenger.

primary_references

[sil-p11468204] Sildenafil inhibits hypoxia-induced pulmonary hypertension. (2001). https://pubmed.ncbi.nlm.nih.gov/11468204/ DOI: 10.1161/hc2901.093117

tissue_or_cell_type

Pulmonary circulation

trigger_kind

machinery_impairment Imported condition classification; unverified.

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 509–520

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Randomised double-blind hypoxic challenge in ten volunteers with right heart catheterisation, plus isolated perfused lung and chronic hypoxia in wild-type and endothelial nitric oxide synthase deficient mice · source_derived_draft · unverified_draft

### sil-works-without-enos In isolated perfused lung of wild-type and endothelial nitric oxide synthase deficient mice sildenafil markedly blunted acute hypoxic pulmonary vasoconstriction, wild-type mice dosed through three weeks of hypoxia showed a significant reduction in right ventricular systolic pressure from 43.3 to 29.9 millimetres of mercury coupled with a small reduction in right ventricular hypertrophy and inhibition of pulmonary vascular remodelling, while in the knockout mice the drug attenuated the rise in right ventricular systolic pressure but without significant effect on hypertrophy or remodelling, so the endothelial pathway contributes but other biochemical sources of cyclic GMP also play a role. Condition category: machinery_impairment 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 still works when the main source of the upstream signal has been deleted, so something else is supplying the messenger. organism: Mouse tissue_or_cell_type: Pulmonary circulation experimental_model: Randomised double-blind hypoxic challenge in ten volunteers with right heart catheterisation, plus isolated perfused lung and chronic hypoxia in wild-type and endothelial nitric oxide synthase deficient mice limitations: The knockout arm is what makes this decisive about the source of cyclic GMP, and the human arm measures pressure invasively. Ten volunteers, and the mouse exposure is far longer than the human one. exposure: Sildenafil 100 milligrams orally before 11 percent oxygen for 30 minutes, and 25 milligrams per kilogram daily through three weeks of 10 percent oxygen in mice evidence_span: {"source_cache": "artifacts/sildenafil-research/11468204.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "41d880663288811422c4400d86de1eedd4d5b254d8bb3a59a8fbff01dedbcb24", "start_char": 0, "end_char": 1820, "text_sha256": "41d880663288811422c4400d86de1eedd4d5b254d8bb3a59a8fbff01dedbcb24"} [sil-p11468204] Sildenafil inhibits hypoxia-induced pulmonary hypertension. (2001). https://pubmed.ncbi.nlm.nih.gov/11468204/ DOI: 10.1161/hc2901.093117

duration

Acute

evidence_access

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

experimental_model

cGMP-dependent kinase I null mice compared with normal mice

exposure

Activation of the NO/cGMP cascade

limitations

A whole-body knockout rather than tissue-specific deletion; the mice also had a very low ability to reproduce, while their sperm were normal and could fertilise eggs.

organism

cGMP-dependent kinase I null mice compared with normal mice

plain_language

Corpora cavernosa from mice lacking cGMP-dependent kinase I failed to relax when the nitric oxide and cGMP signalling cascade was activated.

primary_references

Erectile dysfunction in cyclic GMP-dependent kinase I-deficient mice. (2000). https://pubmed.ncbi.nlm.nih.gov/10688876/ DOI: 10.1073/pnas.030419997

route

Isolated tissue

tissue

Corpus cavernosum smooth muscle relaxation

Tadalafil: PDE5 occupancy, the cGMP route and three measured endpoints (2026-09-22) · lines 56–65

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

## cgmp-dependent-kinase-i-carries-the-relaxation Corpora cavernosa from mice lacking cGMP-dependent kinase I failed to relax when the nitric oxide and cGMP signalling cascade was activated. Model/species: cGMP-dependent kinase I null mice compared with normal mice Tissue/system: Corpus cavernosum smooth muscle relaxation Exposure: Activation of the NO/cGMP cascade Route: Isolated tissue Duration: Acute Limits: A whole-body knockout rather than tissue-specific deletion; the mice also had a very low ability to reproduce, while their sperm were normal and could fertilise eggs. Primary reference: Erectile dysfunction in cyclic GMP-dependent kinase I-deficient mice. (2000). https://pubmed.ncbi.nlm.nih.gov/10688876/ DOI: 10.1073/pnas.030419997 Access: Primary PubMed abstract and indexed metadata reviewed. Full-text method details not stated here remain unresolved.

duration

Acute

evidence_access

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

experimental_model

cGMP-dependent kinase I null mice compared with normal mice

exposure

Forskolin

limitations

Shows an intact parallel cAMP route in isolated tissue; the authors conclude cAMP signalling cannot compensate for the absent cGMP cascade in vivo, which is an inference from the reproductive phenotype rather than a separate measurement.

organism

cGMP-dependent kinase I null mice compared with normal mice

plain_language

Raising cyclic AMP with forskolin produced similar relaxation in normal and cGMP-dependent kinase I null corpus cavernosum.

primary_references

Erectile dysfunction in cyclic GMP-dependent kinase I-deficient mice. (2000). https://pubmed.ncbi.nlm.nih.gov/10688876/ DOI: 10.1073/pnas.030419997

route

Isolated tissue

tissue

Corpus cavernosum smooth muscle relaxation

Tadalafil: PDE5 occupancy, the cGMP route and three measured endpoints (2026-09-22) · lines 67–76

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

## cyclic-amp-does-not-substitute-for-the-cgmp-route Raising cyclic AMP with forskolin produced similar relaxation in normal and cGMP-dependent kinase I null corpus cavernosum. Model/species: cGMP-dependent kinase I null mice compared with normal mice Tissue/system: Corpus cavernosum smooth muscle relaxation Exposure: Forskolin Route: Isolated tissue Duration: Acute Limits: Shows an intact parallel cAMP route in isolated tissue; the authors conclude cAMP signalling cannot compensate for the absent cGMP cascade in vivo, which is an inference from the reproductive phenotype rather than a separate measurement. Primary reference: Erectile dysfunction in cyclic GMP-dependent kinase I-deficient mice. (2000). https://pubmed.ncbi.nlm.nih.gov/10688876/ DOI: 10.1073/pnas.030419997 Access: Primary PubMed abstract and indexed metadata reviewed. Full-text method details not stated here remain unresolved.

duration

Measured to 96 hours after the last tadalafil dose

evidence_access

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

experimental_model

150 male subjects, randomised crossover with a 10 to 21 day washout

exposure

Seven consecutive daily doses of tadalafil 20 mg or placebo, then repeated sublingual nitroglycerin 0.4 mg

limitations

A pharmacodynamic interaction study in male volunteers using a fixed 20 mg dose; the time course reported here describes when the interaction was detectable, not a dosing instruction.

organism

150 male subjects, randomised crossover with a 10 to 21 day washout

plain_language

After tadalafil, sublingual nitroglycerin lowered standing systolic blood pressure below 85 mmHg in more subjects than after placebo at 4, 8 and 24 hours, with no difference at 48, 72 and 96 hours.

primary_references

Time course of the interaction between tadalafil and nitrates. (2003). https://pubmed.ncbi.nlm.nih.gov/14642699/ DOI: 10.1016/j.jacc.2003.09.023

route

Oral tadalafil with sublingual nitroglycerin

tissue

Standing systolic and diastolic blood pressure after a nitrate

Tadalafil: PDE5 occupancy, the cGMP route and three measured endpoints (2026-09-22) · lines 89–98

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-augments-the-nitrate-blood-pressure-fall After tadalafil, sublingual nitroglycerin lowered standing systolic blood pressure below 85 mmHg in more subjects than after placebo at 4, 8 and 24 hours, with no difference at 48, 72 and 96 hours. Model/species: 150 male subjects, randomised crossover with a 10 to 21 day washout Tissue/system: Standing systolic and diastolic blood pressure after a nitrate Exposure: Seven consecutive daily doses of tadalafil 20 mg or placebo, then repeated sublingual nitroglycerin 0.4 mg Route: Oral tadalafil with sublingual nitroglycerin Duration: Measured to 96 hours after the last tadalafil dose Limits: A pharmacodynamic interaction study in male volunteers using a fixed 20 mg dose; the time course reported here describes when the interaction was detectable, not a dosing instruction. Primary reference: Time course of the interaction between tadalafil and nitrates. (2003). https://pubmed.ncbi.nlm.nih.gov/14642699/ DOI: 10.1016/j.jacc.2003.09.023 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.

duration

16 weeks, double-blind placebo-controlled

evidence_access

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

experimental_model

405 patients with idiopathic or associated pulmonary arterial hypertension, treatment-naive or on background bosentan

exposure

Tadalafil 2.5, 10, 20 or 40 mg once daily against placebo

limitations

The treatment effect was 44 metres in bosentan-naive patients and 23 metres with confidence intervals crossing zero in those already on bosentan, so the benefit on top of existing endothelin blockade was not established here. PubMed records an erratum for this paper without a resolvable identifier, so the erratum was not read and it is not known whether it altered these figures.

organism

405 patients with idiopathic or associated pulmonary arterial hypertension, treatment-naive or on background bosentan

plain_language

Tadalafil increased six-minute walk distance in a dose-dependent manner in pulmonary arterial hypertension, with a mean placebo-corrected effect of 33 metres, and only the 40 mg dose met the prespecified level of statistical significance.

primary_references

Tadalafil therapy for pulmonary arterial hypertension. (2009). https://pubmed.ncbi.nlm.nih.gov/19470885/ DOI: 10.1161/CIRCULATIONAHA.108.839274

route

Oral

tissue

Six-minute walk distance, WHO functional class and clinical worsening

Tadalafil: PDE5 occupancy, the cGMP route and three measured endpoints (2026-09-22) · lines 100–109

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-six-minute-walk-in-pulmonary-arterial-hypertension Tadalafil increased six-minute walk distance in a dose-dependent manner in pulmonary arterial hypertension, with a mean placebo-corrected effect of 33 metres, and only the 40 mg dose met the prespecified level of statistical significance. Model/species: 405 patients with idiopathic or associated pulmonary arterial hypertension, treatment-naive or on background bosentan Tissue/system: Six-minute walk distance, WHO functional class and clinical worsening Exposure: Tadalafil 2.5, 10, 20 or 40 mg once daily against placebo Route: Oral Duration: 16 weeks, double-blind placebo-controlled Limits: The treatment effect was 44 metres in bosentan-naive patients and 23 metres with confidence intervals crossing zero in those already on bosentan, so the benefit on top of existing endothelin blockade was not established here. PubMed records an erratum for this paper without a resolvable identifier, so the erratum was not read and it is not known whether it altered these figures. Primary reference: Tadalafil therapy for pulmonary arterial hypertension. (2009). https://pubmed.ncbi.nlm.nih.gov/19470885/ DOI: 10.1161/CIRCULATIONAHA.108.839274 Access: Primary PubMed abstract and indexed metadata reviewed. Full-text method details not stated here remain unresolved.

evidence_access

Primary full text

experimental_model

Isolated rat pituitary; tissue plus medium assays.

limitations

The association does not alone prove cGMP is the exclusive causal mediator; not direct human pituitary evidence.

nutrient_topic

D-Aspartate collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · D-Aspartate

plain_language

A rat tissue experiment links the response to a second-messenger change.

primary_references

The role and molecular mechanism of D-aspartic acid in the release and synthesis of LH and testosterone in humans and rats. · 2009 · https://pubmed.ncbi.nlm.nih.gov/19860889/ · DOI 10.1186/1477-7827-7-120

D-Aspartate: synthesis, clearance, neural and endocrine mechanisms (2026-09-19) · lines 368–374

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Isolated rat pituitary; tissue plus medium assays. · source_derived_draft · unverified_draft

## d-aspartate-rat-pituitary-lh A rat tissue experiment links the response to a second-messenger change. Rat pituitary incubation with 0.1 or 1 mM D-aspartate increased measured LH and cGMP over 60 minutes. Model: Isolated rat pituitary; tissue plus medium assays. Limitations: The association does not alone prove cGMP is the exclusive causal mediator; not direct human pituitary evidence. Evidence access: Primary full text The role and molecular mechanism of D-aspartic acid in the release and synthesis of LH and testosterone in humans and rats. · 2009 · https://pubmed.ncbi.nlm.nih.gov/19860889/ · DOI 10.1186/1477-7827-7-120

evidence_span

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experimental_model

Double-blind placebo-controlled crossover study

exposure

Citrulline 0.75, 1.5 or 3 g twice daily versus arginine formulations; one-week periods

limitations

Small short trial; NO-related urine markers do not establish a clinically meaningful vascular benefit.

nutrient_topic

Citrulline research collection; topical membership is not evidence of a direct dietary effect. · L-Citrulline

organism

Human, 20 healthy volunteers

plain_language

The substrate-to-inhibitor ratio changed; this does not mean ADMA itself was removed.

primary_references

[citrulline-p17662090] Pharmacokinetic and pharmacodynamic properties of oral L-citrulline and L-arginine: impact on nitric oxide metabolism. (2008). https://pubmed.ncbi.nlm.nih.gov/17662090/ DOI: 10.1111/j.1365-2125.2007.02990.x

tissue_or_cell_type

Plasma amino acids, urine NO markers and brachial FMD

Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 879–890

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Double-blind placebo-controlled crossover study · source_derived_draft · unverified_draft

### citrulline-adma-ratio At 3 g twice daily, the arginine/ADMA ratio rose from 186 to 278. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: The substrate-to-inhibitor ratio changed; this does not mean ADMA itself was removed. organism: Human, 20 healthy volunteers tissue_or_cell_type: Plasma amino acids, urine NO markers and brachial FMD experimental_model: Double-blind placebo-controlled crossover study limitations: Small short trial; NO-related urine markers do not establish a clinically meaningful vascular benefit. exposure: Citrulline 0.75, 1.5 or 3 g twice daily versus arginine formulations; one-week periods evidence_span: {"source_cache": "artifacts/citrulline-research/17662090.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "32e6ddf6d263120576f0f73c7fe3dd104904f3c0ba0a1c3f69cdca5751c4fa3b", "start_char": 0, "end_char": 1980, "text_sha256": "32e6ddf6d263120576f0f73c7fe3dd104904f3c0ba0a1c3f69cdca5751c4fa3b"} [citrulline-p17662090] Pharmacokinetic and pharmacodynamic properties of oral L-citrulline and L-arginine: impact on nitric oxide metabolism. (2008). https://pubmed.ncbi.nlm.nih.gov/17662090/ DOI: 10.1111/j.1365-2125.2007.02990.x

evidence_span

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experimental_model

Double-blind placebo-controlled crossover study

exposure

Citrulline 0.75, 1.5 or 3 g twice daily versus arginine formulations; one-week periods

limitations

Small short trial; NO-related urine markers do not establish a clinically meaningful vascular benefit.

nutrient_topic

Citrulline research collection; topical membership is not evidence of a direct dietary effect. · L-Citrulline

organism

Human, 20 healthy volunteers

plain_language

Better precursor exposure did not produce a detectable improvement in this vascular endpoint.

primary_references

[citrulline-p17662090] Pharmacokinetic and pharmacodynamic properties of oral L-citrulline and L-arginine: impact on nitric oxide metabolism. (2008). https://pubmed.ncbi.nlm.nih.gov/17662090/ DOI: 10.1111/j.1365-2125.2007.02990.x

tissue_or_cell_type

Plasma amino acids, urine NO markers and brachial FMD

Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 918–929

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Double-blind placebo-controlled crossover study · source_derived_draft · unverified_draft

### citrulline-healthy-fmd-null No treatment improved FMD over baseline in the healthy-volunteer study. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: Better precursor exposure did not produce a detectable improvement in this vascular endpoint. organism: Human, 20 healthy volunteers tissue_or_cell_type: Plasma amino acids, urine NO markers and brachial FMD experimental_model: Double-blind placebo-controlled crossover study limitations: Small short trial; NO-related urine markers do not establish a clinically meaningful vascular benefit. exposure: Citrulline 0.75, 1.5 or 3 g twice daily versus arginine formulations; one-week periods evidence_span: {"source_cache": "artifacts/citrulline-research/17662090.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "32e6ddf6d263120576f0f73c7fe3dd104904f3c0ba0a1c3f69cdca5751c4fa3b", "start_char": 0, "end_char": 1980, "text_sha256": "32e6ddf6d263120576f0f73c7fe3dd104904f3c0ba0a1c3f69cdca5751c4fa3b"} [citrulline-p17662090] Pharmacokinetic and pharmacodynamic properties of oral L-citrulline and L-arginine: impact on nitric oxide metabolism. (2008). https://pubmed.ncbi.nlm.nih.gov/17662090/ DOI: 10.1111/j.1365-2125.2007.02990.x

evidence_span

{"source_cache": "artifacts/citrulline-research/17662090.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "32e6ddf6d263120576f0f73c7fe3dd104904f3c0ba0a1c3f69cdca5751c4fa3b", "start_char": 0, "end_char": 1980, "text_sha256": "32e6ddf6d263120576f0f73c7fe3dd104904f3c0ba0a1c3f69cdca5751c4fa3b"}

experimental_model

Double-blind placebo-controlled crossover study

exposure

Citrulline 0.75, 1.5 or 3 g twice daily versus arginine formulations; one-week periods

limitations

Small short trial; NO-related urine markers do not establish a clinically meaningful vascular benefit.

nutrient_topic

Citrulline research collection; topical membership is not evidence of a direct dietary effect. · L-Citrulline

organism

Human, 20 healthy volunteers

plain_language

Taking the precursor can raise circulating arginine efficiently.

primary_references

[citrulline-p17662090] Pharmacokinetic and pharmacodynamic properties of oral L-citrulline and L-arginine: impact on nitric oxide metabolism. (2008). https://pubmed.ncbi.nlm.nih.gov/17662090/ DOI: 10.1111/j.1365-2125.2007.02990.x

tissue_or_cell_type

Plasma amino acids, urine NO markers and brachial FMD

Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 866–877

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Double-blind placebo-controlled crossover study · source_derived_draft · unverified_draft

### citrulline-oral-arginine Oral citrulline increased plasma arginine AUC and peak concentration dose-dependently, more effectively than the tested oral arginine regimens. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: Taking the precursor can raise circulating arginine efficiently. organism: Human, 20 healthy volunteers tissue_or_cell_type: Plasma amino acids, urine NO markers and brachial FMD experimental_model: Double-blind placebo-controlled crossover study limitations: Small short trial; NO-related urine markers do not establish a clinically meaningful vascular benefit. exposure: Citrulline 0.75, 1.5 or 3 g twice daily versus arginine formulations; one-week periods evidence_span: {"source_cache": "artifacts/citrulline-research/17662090.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "32e6ddf6d263120576f0f73c7fe3dd104904f3c0ba0a1c3f69cdca5751c4fa3b", "start_char": 0, "end_char": 1980, "text_sha256": "32e6ddf6d263120576f0f73c7fe3dd104904f3c0ba0a1c3f69cdca5751c4fa3b"} [citrulline-p17662090] Pharmacokinetic and pharmacodynamic properties of oral L-citrulline and L-arginine: impact on nitric oxide metabolism. (2008). https://pubmed.ncbi.nlm.nih.gov/17662090/ DOI: 10.1111/j.1365-2125.2007.02990.x

evidence_span

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experimental_model

Double-blind placebo-controlled crossover study

exposure

Citrulline 0.75, 1.5 or 3 g twice daily versus arginine formulations; one-week periods

limitations

Small short trial; NO-related urine markers do not establish a clinically meaningful vascular benefit.

nutrient_topic

Citrulline research collection; topical membership is not evidence of a direct dietary effect. · L-Citrulline

organism

Human, 20 healthy volunteers

plain_language

A downstream signaling marker increased.

primary_references

[citrulline-p17662090] Pharmacokinetic and pharmacodynamic properties of oral L-citrulline and L-arginine: impact on nitric oxide metabolism. (2008). https://pubmed.ncbi.nlm.nih.gov/17662090/ DOI: 10.1111/j.1365-2125.2007.02990.x

tissue_or_cell_type

Plasma amino acids, urine NO markers and brachial FMD

Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 892–903

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Double-blind placebo-controlled crossover study · source_derived_draft · unverified_draft

### citrulline-urine-cgmp The highest citrulline regimen increased urinary cGMP from 38 to 50 nmol/mmol creatinine. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: A downstream signaling marker increased. organism: Human, 20 healthy volunteers tissue_or_cell_type: Plasma amino acids, urine NO markers and brachial FMD experimental_model: Double-blind placebo-controlled crossover study limitations: Small short trial; NO-related urine markers do not establish a clinically meaningful vascular benefit. exposure: Citrulline 0.75, 1.5 or 3 g twice daily versus arginine formulations; one-week periods evidence_span: {"source_cache": "artifacts/citrulline-research/17662090.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "32e6ddf6d263120576f0f73c7fe3dd104904f3c0ba0a1c3f69cdca5751c4fa3b", "start_char": 0, "end_char": 1980, "text_sha256": "32e6ddf6d263120576f0f73c7fe3dd104904f3c0ba0a1c3f69cdca5751c4fa3b"} [citrulline-p17662090] Pharmacokinetic and pharmacodynamic properties of oral L-citrulline and L-arginine: impact on nitric oxide metabolism. (2008). https://pubmed.ncbi.nlm.nih.gov/17662090/ DOI: 10.1111/j.1365-2125.2007.02990.x

evidence_span

{"source_cache": "artifacts/citrulline-research/17662090.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "32e6ddf6d263120576f0f73c7fe3dd104904f3c0ba0a1c3f69cdca5751c4fa3b", "start_char": 0, "end_char": 1980, "text_sha256": "32e6ddf6d263120576f0f73c7fe3dd104904f3c0ba0a1c3f69cdca5751c4fa3b"}

experimental_model

Double-blind placebo-controlled crossover study

exposure

Citrulline 0.75, 1.5 or 3 g twice daily versus arginine formulations; one-week periods

limitations

Small short trial; NO-related urine markers do not establish a clinically meaningful vascular benefit.

nutrient_topic

Citrulline research collection; topical membership is not evidence of a direct dietary effect. · L-Citrulline

organism

Human, 20 healthy volunteers

plain_language

Another NO-related marker changed.

primary_references

[citrulline-p17662090] Pharmacokinetic and pharmacodynamic properties of oral L-citrulline and L-arginine: impact on nitric oxide metabolism. (2008). https://pubmed.ncbi.nlm.nih.gov/17662090/ DOI: 10.1111/j.1365-2125.2007.02990.x

tissue_or_cell_type

Plasma amino acids, urine NO markers and brachial FMD

Citrulline: arginine recycling, nitrogen disposal and nutrient connections (2026-09-17) · lines 905–916

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Double-blind placebo-controlled crossover study · source_derived_draft · unverified_draft

### citrulline-urine-nitrate The highest regimen increased urinary nitrate from 92 to 125 micromol/mmol creatinine. Condition category: normal nutrient_topic: Citrulline research collection; topical membership is not evidence of a direct dietary effect. plain_language: Another NO-related marker changed. organism: Human, 20 healthy volunteers tissue_or_cell_type: Plasma amino acids, urine NO markers and brachial FMD experimental_model: Double-blind placebo-controlled crossover study limitations: Small short trial; NO-related urine markers do not establish a clinically meaningful vascular benefit. exposure: Citrulline 0.75, 1.5 or 3 g twice daily versus arginine formulations; one-week periods evidence_span: {"source_cache": "artifacts/citrulline-research/17662090.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "32e6ddf6d263120576f0f73c7fe3dd104904f3c0ba0a1c3f69cdca5751c4fa3b", "start_char": 0, "end_char": 1980, "text_sha256": "32e6ddf6d263120576f0f73c7fe3dd104904f3c0ba0a1c3f69cdca5751c4fa3b"} [citrulline-p17662090] Pharmacokinetic and pharmacodynamic properties of oral L-citrulline and L-arginine: impact on nitric oxide metabolism. (2008). https://pubmed.ncbi.nlm.nih.gov/17662090/ DOI: 10.1111/j.1365-2125.2007.02990.x

cross_nutrient

Calcium-sensitive GCAPs regulate recovery downstream of the vitamin A photopigment.

experimental_model

Retinal homogenate cyclase activity at low versus high free calcium

limitations

Evidence for intracellular feedback, not calcium intake or blood-calcium thresholds.

nutrient_topic

Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A

organism

Mus musculus

plain_language

GCAP sensors connect calcium changes to cGMP synthesis.

primary_references

[mendez-2001] Role of guanylate cyclase-activating proteins (GCAPs) in setting the flash sensitivity of rod photoreceptors (2001). https://pmc.ncbi.nlm.nih.gov/articles/PMC55558/ DOI: 10.1073/pnas.171308998

tissue_or_cell_type

Retina

Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 961–971

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Retinal homogenate cyclase activity at low versus high free calcium · source_derived_draft · unverified_draft

### a-vision-calcium-cyclase-feedback Removing GCAP1 and GCAP2 abolished calcium dependence of retinal guanylyl cyclase activity in mouse assays. Condition category: normal nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: GCAP sensors connect calcium changes to cGMP synthesis. organism: Mus musculus tissue_or_cell_type: Retina experimental_model: Retinal homogenate cyclase activity at low versus high free calcium limitations: Evidence for intracellular feedback, not calcium intake or blood-calcium thresholds. cross_nutrient: Calcium-sensitive GCAPs regulate recovery downstream of the vitamin A photopigment. [mendez-2001] Role of guanylate cyclase-activating proteins (GCAPs) in setting the flash sensitivity of rod photoreceptors (2001). https://pmc.ncbi.nlm.nih.gov/articles/PMC55558/ DOI: 10.1073/pnas.171308998

cross_nutrient

Mg2+ and Ca2+ regulate a sensor in vitamin A-dependent phototransduction recovery.

experimental_model

Purified protein metal-binding and cyclase assays

limitations

No dietary magnesium deficiency or human night-vision outcome was measured.

nutrient_topic

Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A

organism

Recombinant protein biochemical system

plain_language

Magnesium occupancy lets the calcium sensor stimulate cGMP recovery.

primary_references

[peshenko-2006] Ca2+ and Mg2+ binding properties of GCAP-1. Evidence that Mg2+-bound form is the physiological activator of photoreceptor guanylyl cyclase (2006). https://pubmed.ncbi.nlm.nih.gov/16793776/ DOI: 10.1074/jbc.M600257200

tissue_or_cell_type

Photoreceptor-protein model

Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 973–983

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified protein metal-binding and cyclase assays · source_derived_draft · unverified_draft

### a-vision-magnesium-gcap1 Magnesium-bound GCAP1, rather than metal-free GCAP1, activated RetGC1 under low-calcium assay conditions. Condition category: normal nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: Magnesium occupancy lets the calcium sensor stimulate cGMP recovery. organism: Recombinant protein biochemical system tissue_or_cell_type: Photoreceptor-protein model experimental_model: Purified protein metal-binding and cyclase assays limitations: No dietary magnesium deficiency or human night-vision outcome was measured. cross_nutrient: Mg2+ and Ca2+ regulate a sensor in vitamin A-dependent phototransduction recovery. [peshenko-2006] Ca2+ and Mg2+ binding properties of GCAP-1. Evidence that Mg2+-bound form is the physiological activator of photoreceptor guanylyl cyclase (2006). https://pubmed.ncbi.nlm.nih.gov/16793776/ DOI: 10.1074/jbc.M600257200

experimental_model

Reconstituted transducin/PDE assays

limitations

Rod PDE6 complex identity is kept separate from cone PDE6.

nutrient_topic

Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A

organism

Bos taurus

plain_language

Transducin turns on the enzyme that removes cGMP.

primary_references

[fung-1981] Flow of information in the light-triggered cyclic nucleotide cascade of vision (1981). https://pubmed.ncbi.nlm.nih.gov/6264430/ DOI: 10.1073/pnas.78.1.152

tissue_or_cell_type

Rod outer-segment proteins

Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 916–925

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Reconstituted transducin/PDE assays · source_derived_draft · unverified_draft

### a-vision-transducin-pde6 Activated transducin stimulated rod cyclic-GMP phosphodiesterase in the reconstituted signaling system. Condition category: normal nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: Transducin turns on the enzyme that removes cGMP. organism: Bos taurus tissue_or_cell_type: Rod outer-segment proteins experimental_model: Reconstituted transducin/PDE assays limitations: Rod PDE6 complex identity is kept separate from cone PDE6. [fung-1981] Flow of information in the light-triggered cyclic nucleotide cascade of vision (1981). https://pubmed.ncbi.nlm.nih.gov/6264430/ DOI: 10.1073/pnas.78.1.152

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