Sildenafil Inhibits β-Adrenergic–Stimulated Cardiac Contractility in Humans

Abstract

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 ␤-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, nϭ19) or placebo (nϭ16). 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 80Ϯ28% in the placebo group and 82Ϯ31% in the sildenafil group; PϭNS). 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 32Ϯ34%, 66Ϯ64%, and 56Ϯ63%, respectively (each PϽ0.001 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.

Pre‐operative sildenafil and pulmonary endothelial‐related complications following cardiopulmonary bypass: a randomised trial in children undergoing cardiac surgery*

“…Experimental models of isolated cardiomyocytes and perfused rodent hearts, and human studies of normal and heart failure patients at the time of cardiac catheterisation, have shown that elevated levels of cGMP (produced through inhaled inducible NO or oral sildenafil) can suppress contractility by decreasing myocardial calcium sensitivity, inhibiting cyclic adenosine monophosphate and blunting the contractile response to adrenergic stimulation [17,[22][23][24]. Although peri-operative cGMP was similar between groups in this study, alterations to cyclic adenosine monophosphate, myocardial calcium handling and endogenous catecholamine levels were not investigated and could account for the significant contractile deficit in sildenafil patients.…”

Pivotal effects of phosphodiesterase inhibitors on myocyte contractility and viability in normal and ischemic hearts

“…Instead, it can be explained by reflex sympathetic stimulation caused by vasodilation. Indeed, in humans, sildenafil reduces vagal modulation and increases sympathetic stimulation of the heart [187] and also slightly increases contractility in healthy human volunteers [188] although the effect in this study is suspect since the measurements were taken 75 min follow ing dobutamine infusion. Sildenafil-induced sympathetic activation seems to be general, as shown by increases in plasma norepinephrine levels and muscle sympathetic nerve activity [189] .…”

“…This effect was not observed in eNOS knockout mice but was restored with adenoviral transfer of active eNOS [181] . Sildenafil also slightly attenuated the isoproterenol-induced increase in force of contraction in human myocardial tissue [190] , and contractile response to dobutamine was blunted by sildenafil in healthy human volunteers [188] .…”

Impact of Comorbidities on Myocardial Remodeling and Dysfunction In Heart Failure with Preserved Ejection Fraction

“…PDE5A inhibitors attenuate adrenergic stimulation [209], reduce ventricularvascular stiffening [209], antagonize maladaptive chamber …”