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

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 mu M angiotensin II was approximately 35% greater than in control animals. This finding was observed concomitantly with ail 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 p M) were constructed before and after the addition of prazosin (alpha-I 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 I-125-angiotensin II. Age-matched golden hamsters were used as controls (CT). Our results indicate that incubation with either 10 mu M prazosin or 10 PM NS-398 did not modify EC50 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 mu M BQ-123 reduced by 40% the contraction induced by 1.0 mu M 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 11 is mediated in part by ET-I. At lower angiotensin 11 concentration (0.1 mu M), the ET-I-dependent contraction decreases to 29%. In addition, although dissociation constants for labeled angiotensin 11 were found to be similar in the aorta of SCH and control animals (K-D: CT=7.8 nM and SCH=5.1 nM),. I-125-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 ail increased binding capacity for the hormone and facilitation of the ET-I action. (c) 2006 Elsevier Me. All rights reserved.