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on April 22, 2004

Arteriosclerosis, Thrombosis, and Vascular Biology. 2004
Published online before print April 22, 2004, doi: 10.1161/01.ATV.0000129331.21092.1d
A more recent version of this article appeared on June 1, 2004
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Submitted on March 25, 2004
Accepted on April 12, 2004

Bradykinin Contributes to the Systemic Hemodynamic Effects of Chronic Angiotensin-Converting Enzyme Inhibition in Patients With Heart Failure

Nicholas L. M. Cruden *; Fraser N. Witherow ; David J. Webb ; Keith A.A. Fox ; and David E. Newby

From the Centre for Cardiovascular Science, University of Edinburgh, Royal Infirmary of Edinburgh, Edinburgh, United Kingdom.

* To whom correspondence should be addressed. E-mail: nick.cruden{at}ed.ac.uk.

Background--Bradykinin is an endogenous vasodilator that may contribute to the systemic effects of angiotensin-converting enzyme (ACE) inhibitor therapy. Using B9340, a bradykinin receptor antagonist, we determined the contribution of bradykinin to the systemic hemodynamic effects of long-term ACE inhibition in patients with chronic heart failure.

Methods and Results--Fourteen patients with heart failure received enalapril (10 mg twice daily) or losartan (50 mg twice daily) in a randomized double-blind crossover trial. After 6 weeks treatment, patients underwent right heart catheterization and were randomized to an intravenous infusion of B9340 (2 to 20 µg/kg per minute) or saline placebo. After B9340 infusion in patients treated with enalapril, mean arterial pressure (+5.2 mm Hg), systemic vascular resistance (+315 dynes·s/cm5), pulmonary arterial wedge pressure (-1.4 mm Hg), and mean pulmonary arterial pressure (-1.3 mm Hg) were greater compared with losartan (P<0.005, P=0.07, P<0.0001, and P<0.05 respectively) or placebo infusion (P<=0.005 for all). There was a reduction in cardiac output after B9340 with enalapril compared with placebo (P<0.001) but not losartan.

Conclusions--Bradykinin contributes to the systemic hemodynamic effects of long-term ACE inhibition in patients with heart failure. This mechanism may explain the apparent clinical differences between ACE inhibitors and angiotensin receptor blockers in the treatment of heart failure.
Key words: ACE inhibitors • bradykinin • heart failure • hemodynamics • pharmacology




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