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Clinical Science (2005) 108, (331–338) (Printed in Great Britain)

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Inhibition of angiotensin-converting enzyme and phosphodiesterase type 5 improves endothelial function in heart failure

Katarzyna HRYNIEWICZ*, Clarito DIMAYUGA†, Alhakam HUDAIHED*, Ana Silvia ANDRONE*, Haoyi ZHENG*, Krzysztof JANKOWSKI‡ and Stuart D. KATZ*

*Department of Internal Medicine, Section of Cardiovascular Medicine, Yale University School of Medicine, New Haven, CT 06510, U.S.A., †Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY 10032, U.S.A., and ‡Department of Internal Medicine and Cardiology, Warsaw University, Warsaw, Poland

Key words: angiotensin-converting enzyme (ACE), heart failure, endothelium, nitric oxide, neurohormone, phosphodiesterase (PDE).

Abbreviations: ACE, angiotensin-converting enzyme; ARB, angiotensin-receptor blocker; BNP, brain natriuretic peptide; CHF, chronic heart failure; FMD, flow-mediated dilation; HR, heart rate; MAP, mean arterial pressure; MBFV, mean blood flow velocity; NO, nitric oxide; NYHA, New York Heart Association; PDE5, phosphodiesterase type 5.

Correspondence: Dr Stuart D. Katz (email stuart.katz@yale.edu).

ACE (angiotensin-converting enzyme) inhibitors and PDE5 (phosphodiesterase type 5) inhibitors have each been reported to improve endothelial function in cardiovascular disease patients, but the comparative and combined effects of these two classes have not been studied previously. We sought to characterize the acute effects of ramipril alone, sildenafil alone, or their combination on endothelial function in patients with CHF (chronic heart failure). CHF subjects (n=64) were randomized to receive placebo, 10 mg of ramipril alone, 50 mg of sildenafil alone or a combination of ramipril and sildenafil in a double-blind manner. FMD (flow-mediated dilation) of the brachial artery was determined by high-resolution ultrasound imaging before and at 1, 2 and 4 h after administration of the study drug. Ramipril alone increased FMD at 4 h compared with placebo (+2.3±1.3%, P=0.02). Sildenafil alone increased FMD at 1, 2 and 4 h compared with placebo (+3.9±1.4, +4.6±1.8 and +3.7±1.3% respectively, all P<0.02). Sildenafil in combination with ramipril increased FMD at 1, 2 and 4 h when compared with placebo (+3.5±1.5, +4.5±1.8 and +4.8±1.3% respectively, all P<0.03). Ramipril and sildenafil both acutely improved FMD in patients with CHF, with additive effects evident at 4 h during combination therapy. Therefore further work to characterize chronic effects of combined ACE and PDE5 inhibition on endothelial function are warranted.

Received 2 September 2004/23 November 2004; accepted 2 December 2004

Published as Immediate Publication 2 December 2004, DOI 10.1042/CS20040266

©2005 The Biochemical Society