Published Online
on September 12, 2005

A more recent version of this article appeared on October 1, 2005

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Submitted on April 26, 2005
Revised on May 9, 2005

Early Endothelin-A Receptor Blockade Decreases Blood Pressure and Ameliorates End-Organ Damage in Homozygous Ren-2 Rats

Ivana Vanêková^*; Herbert J. Kramer; Angela Bäcker; Zdena Vernerová; Martin Opoensk; and Ludêk ervenka

From Center for Experimental Medicine (I.V., Z.V., M.O., L.C.), Institute for Clinical and Experimental Medicine, Prague, Czech Republic; Cardiovascular Research Center (I.V., Z.V., M.O., L.C.), Prague, Czech Republic; Section of Nephrology (H.J.K., A.B.), Medical Policlinic, University of Bonn, Germany; Department of Pathology (Z.V.), 3rd Medical Faculty, Charles University, Prague, Czech Republic.

^* To whom correspondence should be addressed. E-mail: ivvn{at}medicon.cz.

Abstract--We have recently found that nonselective endothelin ET_A/ET_B receptor blockade markedly improves survival rate and ameliorates end-organ damage in male homozygous rats transgenic (TGR) for the mouse Ren-2 renin gene without lowering blood pressure. Because activation of the ET_A receptor may be responsible for the detrimental effects of ET in the development of hypertension, this study was performed to determine whether ET_A or ET_A/ET_B receptor blockade exerts these beneficial effects. TGR and age-matched normotensive Hannover Sprague-Dawley rats fed a high-salt diet received either vehicle or bosentan and atrasentan (ABT-627) as nonselective ET_A/ET_B and selective ET_A receptor blockers, respectively, from 29 until 90 days of age. The survival rate of 48% in untreated TGR was significantly (P<0.01) improved to 79% by bosentan and to 92% by ABT-627 (ABT-627 versus bosentan P<0.05). Proteinuria, glomerulosclerosis, and cardiac hypertrophy, as well as ET-1 content in left ventricular tissue, were significantly reduced by bosentan and to a greater degree by ABT-627, which also significantly attenuated the rise in blood pressure (P<0.05). Our data indicate that the ET system, especially via ET_A receptors, plays an important role in the development of hypertensive end-organ damage and confirm the concept that the predominant role of ET_B receptors within the peripheral vasculature is to mediate the vasorelaxant actions of ET-1. They also demonstrate that selective blockade of ET_A receptors is superior to nonselective ET_A/ET_B in attenuating hypertension, hypertensive organ damage, and survival rate.

Key words: hypertension • kidney • antihypertensive drugs • end-organ damage • systolic • experimental models

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