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(Circulation. 2000;102:351.)
© 2000 American Heart Association, Inc.
Basic Science Reports |
Improvement of Endothelial Function by Chronic Angiotensin-Converting Enzyme Inhibition in Heart Failure
Role of Nitric Oxide, Prostanoids, Oxidant Stress, and Bradykinin
From the Department of Pharmacology, Institut National de la Sante et de la Recherche Medicale, INSERM Egg20, Institut Federatif de Recherche Multidisciplinaires sur les Peptides, 23, Rouen University Medical School, Rouen, France.
Correspondence to Prof C. Thuillez, MD, PhD, Service de Pharmacologie, CHU de Rouen, 76031 Rouen, Cedex, France. E-mail Christian.Thuilllez{at}chu-rouen.fr
Background—Chronic heart failure (CHF) impairs the endothelium-dependent, flow-mediated dilation (FMD) of small arteries. However, whether chronic angiotensin-converting enzyme (ACE) inhibition affects the impairment of FMD in CHF is unknown. We investigated the effects of long-term ACE inhibition on the FMD of peripheral arteries in rats with CHF and the mechanism(s) involved.
Methods and Results—FMD was assessed in isolated, perfused gracilis muscle arteries from sham-operated, and untreated or ACE inhibitor-treated (perindopril 2 mg · kg-1 · day-1 for 10 weeks) rats with CHF (coronary artery ligation). The role of nitric oxide (NO), prostaglandins, and free radicals was assessed by pretreating the vessels with the NO synthase inhibitor NW-nitro-L-arginine, the cyclooxygenase inhibitor diclofenac, or the free radical scavenger N-2-mercaptopropionyl-glycine (MPG). Endothelial NO synthase mRNA expression was determined by reverse transcriptase polymerase chain reaction. In animals with hemodynamic and echographic signs of CHF, FMD was converted into vasoconstriction, and this was prevented by ACE inhibition. FMD of arteries from sham-operated or ACE inhibitor–treated CHF rats was abolished by NW-nitro-L-arginine. In untreated CHF rats, FMD was increased by diclofenac and MPG. In contrast, in arteries from ACE inhibitor–treated rats, neither diclofenac nor MPG affected FMD. In parallel, ACE inhibition prevented the reduction of endothelial NO synthase mRNA by CHF.
Conclusions—In CHF, ACE inhibition normalized NO-dependent dilatation and suppressed the production of vasoconstrictor prostanoid(s), resulting in improved FMD. The improvement of FMD might contribute to the beneficial effects of ACE inhibition during CHF.
Key Words: angiotensin-converting enzyme inhibitors • dilatation • heart failure • muscle, skeletal • prostaglandins • nitric oxide synthase • oxidative stress
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