Sildenafil and B-type natriuretic peptide acutely phosphorylate titin and improve diastolic distensibility in vivo

Kalkidan Bishu, Nazha Hamdani, Selma F. Mohammed, Martina Kruger, Tomohito Ohtani, Ozgur Ogut, Frank V. Brozovich, John C. Burnett, Wolfgang A. Linke, Margaret M. Redfield

Research output: Contribution to journalReview article

113 Scopus citations

Abstract

BACKGROUND-: In 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 RESULTS-: Eight 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. CONCLUSION-: Short-term cGMP-enhancing treatment with sildenafil and BNP improves left ventricular diastolic distensibility in vivo, in part by phosphorylating titin.

Original languageEnglish (US)
Pages (from-to)2882-2891
Number of pages10
JournalCirculation
Volume124
Issue number25
DOIs
StatePublished - Dec 20 2011

Keywords

  • Cyclic GMP-dependent protein kinases
  • Heart failure, diastolic
  • Natriuretic peptide
  • Sildenafil
  • brain

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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