Sildenafil inhibits beta-adrenergic-stimulated cardiac contractility in humans.
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 beta-adrenergic or pressure overloads. We therefore tested whether sildenafil blunts dobutamine-stimulated cardiac function in humans.


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 beta-adrenergic stimulation. This finding supports activity of PDE5A in the human heart and its role in modifying stimulated cardiac function.
Borlaug
Barry A
BA
Division of Cardiology, Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, MD 21205, USA.
Melenovsky
Vojtech
V
Marhin
Tricia
T
Fitzgerald
Patricia
P
Kass
David A
DA
D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D003971:Diastole / Q000187:drug effects; D004280:Dobutamine / Q000494:pharmacology; D004311:Double-Blind Method; D004562:Electrocardiography; D006801:Humans; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010879:Piperazines / Q000097:blood / Q000494:pharmacology*; D010919:Placebos; D011687:Purines; D000068677:Sildenafil Citrate; D013450:Sulfones; D013599:Systole / Q000187:drug effects; D014665:Vasodilator Agents / Q000097:blood / Q000494:pharmacology*
D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D010919:Placebos; D011687:Purines; D013450:Sulfones; D014665:Vasodilator Agents; D004280:Dobutamine; D000068677:Sildenafil Citrate; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517381:PDE5A protein, human