Improvement of endothelial function by chronic angiotensin-converting enzyme inhibition in heart failure - Role of nitric oxide, prostanoids, oxidantstress, and bradykinin

Background-Chronic heart failure (CHF) impairs the endothelium-dependent, f low-mediated dilation (FMD) of small arteries. However, wether chronic angi otensin-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) invol ved. Methods and Results-FMD was assessed in isolated, perfused gracilis muscle arteries from sham-operated, and untreated or ACE inhibitor-treated (perind opril 2 mg kg(-1) day(-1) for 10 weeks) rats with CHF (coronary artery liga tion). The role of nitric oxide (NO), prostaglandins, and free radicals was assessed by pretreating the vessels with the NO synthase inhibitor NW-nitr o-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 reacti on. In animals with hemodynamic and echographic signs of CHF, FMD was conve rted into vasoconstriction, and this was prevented by ACE inhibition. FMD o f arteries from sham-operated or ACE inhibitor-treated CHF rats was abolish ed by NW-nitro-L-arginine. In untreated CHF rats, FMD was increased by dicl ofenac and MPG. In contrast, in arteries from ACE inhibitor-treated rats, n either diclofenac nor MPG affected FMD. In parallel, ACE inhibition prevent ed the reduction of endothelial NO synthase mRNA by CHF. Conclusions-In CHF, ACE inhibition normalized NO-dependent dilatation and s uppressed the production of vasoconstrictor prostanoid(s), resulting in imp roved FMD. The improvement of FMD might contribute to the beneficial effect s of ACE inhibition during CHF.