ArticleCirculation2011
Sildenafil and B-type natriuretic peptide acutely phosphorylate titin and improve diastolic distensibility in vivo.
Article in Circulation, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 82 papers.
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Who cites it
82 citing papers in PubMed, 179 citations in OpenAlex.
- Relation of N-terminal pro-B-type natriuretic peptide with diastolic function in hypertensive heart disease.American journal of hypertension · 2013Trial
- PhosphdiesteRasE-5 Inhibition to Improve CLinical Status and EXercise Capacity in Diastolic Heart Failure (RELAX) trial: rationale and design.Circulation. Heart failure · 2012Trial
- Diastolic contributors in cardiomyocytes of a cardiometabolic HFpEF-like mouse model.The Journal of general physiology · 2026Article
- Repaired tetralogy of Fallot across adulthood: from right ventricular remodelling to targeted intervention.Heart failure reviews · 2026Review
- Reversing the pipeline: a 'human-first' multi-omics approach to cardiovascular discovery.Experimental & molecular medicine · 2026Review
- Pitfalls of Therapies Targeting the Nitric Oxide Signaling Pathway in Heart Failure With Preserved Ejection Fraction.Journal of cardiovascular pharmacology · 2026Review
- Comorbidity-Driven Inflammation in HFpEF: Immune Profiling and Therapeutic Targets.Current heart failure reports · 2026Review
- Mending the Achilles heels of titin in cardiac and musculoskeletal disease.Biophysical reviews · 2026Review
- Titin modulation and left ventricular remodelling in chronic primary mitral regurgitation.Frontiers in cardiovascular medicine · 2026Article
- The Potential Connection Between Mechanical Stress and Heart Failure with Preserved Ejection Fraction: Mechanistic Insights and Therapeutic Potential.International journal of medical sciences · 2026Review
- Novel Drug Targets in Diastolic Heart Disease.International journal of molecular sciences · 2025Review
- Direction-dependent contributions of cardiac myofilament networks to myocardial passive stiffness reveal a major disparity for titin.Basic research in cardiology · 2025Article
- Pathophysiological insights into HFpEF from studies of human cardiac tissue.Nature reviews. Cardiology · 2025Review
- Early pathological mechanisms in a mouse model of heart failure with preserved ejection fraction.American journal of physiology. Heart and circulatory physiology · 2024Article
- Empagliflozin and liraglutide ameliorate HFpEF in mice via augmenting the Erbb4 signaling pathway.Acta pharmacologica Sinica · 2024Article
- Rethinking of phosphodiesterase 5 inhibition: the old, the new and the perspective in human health.Frontiers in endocrinology · 2024Review
- Phosphodiesterase-5 Inhibitors as Therapeutics for Cardiovascular Diseases: A Brief Review.Iranian journal of public health · 2023Review
- The NO-cGMP-PKG Axis in HFpEF: From Pathological Mechanisms to Potential Therapies.Aging and disease · 2023Article
- The right ventricle in tetralogy of Fallot: adaptation to sequential loading.Frontiers in pediatrics · 2023Review
- Titin (TTN): from molecule to modifications, mechanics, and medical significance.Cardiovascular research · 2022Review
22 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
10 authors at 1 institution in 1 country.
Funding
Abstract
backgroundIn vitro studies suggest that phosphorylation of titin reduces myocyte/myofiber stiffness. Titin can be phosphorylated by cGMP-activated protein kinase. Intracellular cGMP production is stimulated by B-type natriuretic peptide (BNP) and degraded by phosphodiesterases, including phosphodiesterase-5A. We hypothesized that a phosphodiesterase-5A inhibitor (sildenafil) alone or in combination with BNP would increase left ventricular diastolic distensibility by phosphorylating titin. METHODS AND
resultsEight elderly dogs with experimental hypertension and 4 young normal dogs underwent measurement of the end-diastolic pressure-volume relationship during caval occlusion at baseline, after sildenafil, and BNP infusion. To assess diastolic distensibility independently of load/extrinsic forces, the end-diastolic volume at a common end-diastolic pressure on the sequential end-diastolic pressure-volume relationships was measured (left ventricular capacitance). In a separate group of dogs (n=7 old hypertensive and 7 young normal), serial full-thickness left ventricular biopsies were harvested from the beating heart during identical infusions to measure myofilament protein phosphorylation. Plasma cGMP increased with sildenafil and further with BNP (7.31±2.37 to 26.9±10.3 to 70.3±8.1 pmol/mL; P<0.001). Left ventricular diastolic capacitance increased with sildenafil and further with BNP (51.4±16.9 to 53.7±16.8 to 60.0±19.4 mL; P<0.001). Changes were similar in old hypertensive and young normal dogs. There were no effects on phosphorylation of troponin I, troponin T, phospholamban, or myosin light chain-1 or -2. Titin phosphorylation increased with sildenafil and BNP, whereas titin-based cardiomyocyte stiffness decreased.
conclusionShort-term cGMP-enhancing treatment with sildenafil and BNP improves left ventricular diastolic distensibility in vivo, in part by phosphorylating titin.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.