doi: 10.1161/CIRCULATIONAHA.105.540500
(Circulation. 2005;112:2642-2649.)
© 2005 American Heart Association, Inc.
Heart Failure |
Sildenafil Inhibits ß-Adrenergic–Stimulated Cardiac Contractility in Humans
From the Division of Cardiology, Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, Md.
Correspondence to David A. Kass, MD, Abraham and Virginia Weiss Professor of Cardiology, Johns Hopkins Medical Institutions, Ross 835, 720 Rutland Ave, Baltimore, MD 21205. E-mail dkass{at}jhmi.edu
Received February 5, 2005; revision received May 18, 2005; accepted July 8, 2005.
Background— Sildenafil inhibits phosphodiesterase 5 (PDE5A) to elevate intracellular cGMP and to induce vasodilation. This effect has led to its use for treating erectile dysfunction. Although its influence on rest heart function has appeared minimal, recent animal studies suggest that sildenafil can have potent effects on hearts stimulated by ß-adrenergic or pressure overloads. We therefore tested whether sildenafil blunts dobutamine-stimulated cardiac function in humans.
Methods and Results— Thirty-five healthy volunteers underwent a randomized, double-blind, placebo-controlled study in which cardiac function was assessed in response to dobutamine before and after oral sildenafil (100 mg, n=19) or placebo (n=16). Echo Doppler and noninvasive blood pressure data yielded load-independent contractility indexes (maximal power index and end-systolic elastance), ejection fraction, and measures of diastolic function. In the initial dobutamine test, systolic and diastolic function improved similarly in both treatment groups (eg, peak power index rose 80±28% in the placebo group and 82±31% in the sildenafil group; P=NS). However, in subjects who then received sildenafil, their second dobutamine response was significantly blunted, with peak power, ejection fraction, and end-systolic elastance changes reduced by 32±34%, 66±64%, and 56±63%, respectively (each P<0.001 versus the initial response). This contrasted to the placebo group, which displayed similar functional responses with both dobutamine tests. Sildenafil treatment did not significantly alter diastolic changes induced by dobutamine compared with results with placebo.
Conclusions— PDE5A inhibition by sildenafil blunts systolic responses to ß-adrenergic stimulation. This finding supports activity of PDE5A in the human heart and its role in modifying stimulated cardiac function.
Key Words: contractility • pharmacology • phosphodiesterase 5 • receptors, adrenergic, beta • sildenafil
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