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Sildenafil and B-Type Natriuretic Peptide Acutely Phosphorylate Titin and Improve Diastolic Distensibility In Vivo


[ 作者:Admin     来源:运动解剖学课程网站      点击数:     更新时间:2011/12/30     文章录入:Admin ]



      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.

 

Figure 4.