Increased vascular angiotensin II binding capacity and ET-1 release in young cardiomyopathic hamsters

Abstract

Heart failure (HF) is a multifactorial and progressive disease that has been associated with multiple systemic and vascular alterations. Previous reports from our laboratory showed that in 2-month-old Bio-To2 Syrian cardiomyopathic hamsters (SCH) that have not yet developed the clinical manifestations of HF, the vascular contractility induced by 0.1 μM angiotensin II was approximately 35% greater than in control animals. This finding was observed concomitantly with an increased aortic ACE activity. To further evaluate the mechanisms underlying angiotensin II-enhanced vascular contraction, concentration–response curves for angiotensin II (0.01 nM–10 μM) were constructed before and after the addition of prazosin (alpha-1 blocker), NS-398 (selective COX-2 blocker) and BQ-123 (ET-1 A-receptor antagonist) in aortic rings from 2-month-old SCH. The binding capacity and affinity of the AT-1 receptors were also evaluated in aortic homogenates using 125 I-angiotensin II. Age-matched golden hamsters were used as controls (CT). Our results indicate that incubation with either 10 μM prazosin or 10 μM NS-398 did not modify EC 50 or E max values for angiotensin II indicating that norepinephrine and prostaglandins are not involved in the enhanced contractile action of angiotensin II. However, 10 μM BQ-123 reduced by 40% the contraction induced by 1.0 μM angiotensin II (from 1.05 ± 0.04 to 0.6475 ± 0.06 g/mg tissue, n = 5, P < 0.05), suggesting that in cardiomyopathic hamsters, the action of angiotensin II is mediated in part by ET-1. At lower angiotensin II concentration (0.1 μM), the ET-1-dependent contraction decreases to 29%. In addition, although dissociation constants for labeled angiotensin II were found to be similar in the aorta of SCH and control animals ( K D: CT = 7.8 nM and SCH = 5.1 nM), 125 I-angiotensin II binding capacity was about 2-fold greater in SCH than in controls ( B max: SCH = 1113 and CT = 605 fmol/mg protein). Altogether these results suggest that in 2-month-old SCH the enhanced response of angiotensin II in the vasculature is mediated both by an increased binding capacity for the hormone and facilitation of the ET-1 action.