Comparison of the antagonistic effects of different angiotensin II receptor blockers in human coronary arteries

Abstract

Background: Angiotensin II (Ang II) is a potent vasoconstrictor and a deleterious factor in cardiovascular pathophysiology. Ang II receptor blockers (ARBs) have recently been introduced into clinical practice for treatment of hypertension and congestive heart failure. Aims: This study was undertaken to evaluate the inhibitory effects of ARBs on vasoconstriction in humans. Methods: Vasomotor tone was analyzed in endothelium denuded, human coronary artery (HCA) segments. Ang II type 1 (AT1) and type 2 (AT2) receptor mRNA expression was examined by reverse transcriptase-polymerase chain reaction (RT-PCR). Results: Ang II was a potent vasoconstrictor (pEC50=7.7). At 1 nM of the AT1 receptor antagonists, candesartan and valsartan, the maximum contraction was depressed to 57 and 50% of Ang II, respectively, indicating insurmountability. Although generally considered surmountable, the presence of 100 nM losartan elicited a depression of the Ang II response to 32%. Its active metabolite, EXP 3174 (1 nM), abolished the Ang II contraction. The AT1 receptor antagonists had the following order of blocking effect; EXP 3174>candesartan=valsartan>losartan. The AT2 receptor antagonist, PD 123319 (100 nM) significantly attenuated the Ang II contraction (Emax= 62% of Ang II). RT-PCR of HCA smooth muscle cells demonstrated expression of both AT1 and AT2 receptor mRNA. Conclusions: Ang II contraction in HCA is mediated mainly by AT1 but also involves AT2 receptors. The active metabolite of losartan, EXP 3174, is the most efficacious AT1 receptor antagonist in HCA. © 2002 European Society of Cardiology. Published by Elsevier Science B.V. All rights reserved.