Sildenafil alone and combined with BNP increased left ventricular diastolic capacitance from 51.4 mL at baseline to 53.7 mL and 60.0 mL, respectively (P<0.001), improving diastolic distensibility.
Does sildenafil and BNP infusion improve left ventricular diastolic distensibility in a canine model?
Short-term administration of sildenafil and BNP acutely improves left ventricular diastolic distensibility in vivo, partially through titin phosphorylation.
Absolute Event Rate: 60% vs 51.4%
p-value: p=<0.001
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.
Bishu et al. (Thu,) conducted a other in Experimental hypertension (n=26). Sildenafil and B-Type Natriuretic Peptide (BNP) vs. Baseline was evaluated on Left ventricular diastolic capacitance (p=<0.001). Sildenafil alone and combined with BNP increased left ventricular diastolic capacitance from 51.4 mL at baseline to 53.7 mL and 60.0 mL, respectively (P<0.001), improving diastolic distensibility.