Effects of chronic subdepressor dose of angiotensin II type 1 receptor antagonist on endothelium-dependent vasodilation in patients with congestive heart failure

Abstract

Angiotensin II type 1 receptor antagonist (AIIRA) has been reported to improve exercise capacity and prognosis in patients with congestive heart failure (CHF). However, the effects of AIIRA on peripheral endothelium-dependent and -independent vasodilation remain undefined in this disorder. This study examined the effects and the mechanism of chronic AIIRA therapy on peripheral vasomotion in CHF. Twenty-six patients with CHF were recruited for this study. In protocol 1, 20 patients with CHF were randomly assigned into a losartan (AIIRA) group (n = 10) and a placebo group (n = 10). Forearm blood flow (FBF; ml/min per 100 ml tissue) changes induced by intra-arterial infusion of acetylcholine, sodium nitroprusside, and synthetic angiotensin II were determined by plethysmography before and 3 months after administration of a subdepressor dose of AIIRA or placebo. The goal of protocol 2 was to determine whether the effect of AIIRA is due to a nitric oxide-dependent mechanism in the remaining subset of the CHF group (n = 6). In this group, FBF responses to acetylcholine were examined with and without coadministration of a nitric oxide synthase inhibitor (N(G)-monomethyl->L-arginine; >L-NMMA) either before and 3 months after AIIRA therapy. No significant differences were found in changes in systemic blood pressure and basal FBF among patient groups during the study period. In protocol 1, although in both groups FBF responses induced by sodium nitroprusside as well as angiotensin II remained constant throughout the study, acetylcholine-induced FBF response was significantly enhanced in the losartan group (p < 0.05) but not in the placebo group. In protocol 2, acetylcholine-induced FBF response without >L-NMMA was significantly enhanced after AIIRA administration (p < 0.05), whereas this augmentation effect was diminished under >L-NMMA coinfusion. In conclusion, selective administration of an AIIRA for 3 months improves peripheral endothelium-dependent dilation in patients with CHF. This mechanism may be independent of direct AIIRA effects and may be due, in part, to increased bioavailability of nitric oxide.