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Selective ET_A Receptor Antagonism with ABT-627 Attenuates All Renal Effects of Endothelin in Humans

MARINA L. H. HONING^*,, MICHEL L. HIJMERING^*,, DAVID E. BALLARD, YONGHONG P. YANG, ROBERT J. PADLEY, PAUL J. MORRISON and TON J. RABELINK^*

^* Department of Vascular Medicine and Diabetes, University Hospital Utrecht, The Netherlands
Clinical Pharmacology Unit, Utrecht, The Netherlands
Abbott Laboratories, Abbott Park, Illinois

Correspondence to Dr. Ton J. Rabelink, Department of Vascular Medicine and Diabetes, University Hospital Utrecht, Room F03.226, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands. Phone: +31 30 2507329; Fax: +31 30 2543492; E-mail:T.Rabelink{at}digd.azu.nl

Abstract. Endothelin (ET-1) acts as a potent vasoconstrictor in the human kidney, and this vasoconstriction could contribute to the ischemia seen in acute renal failure. In animal studies, the vasoactive properties of ET-1 are known to be ET_A receptor-and/or ET_B receptor-mediated; however, the receptor subtype involved in the human kidney remains to be defined. In a phase I, single-center, double-blind, randomized, three-period, crossover design, the effects of orally administered ABT-627, a selective ET_A receptor antagonist, on renal hemodynamics during ET-1 infusion were evaluated. Two doses of ABT-627 (5 and 20 mg) were compared with placebo and nifedipine. For each dose level of ABT-627, a cohort of nine subjects was studied. A para-aminohippuric acid/inulin clearance test was performed once at the end of each 7-d treatment period. Infusion of ET-1 significantly decreased effective renal plasma flow, GFR, sodium excretion, and urine flow. Pretreatment with 20 mg of ABT-627 significantly decreased mean arterial pressure. In constrast, 7 d of treatment with both doses of ABT-627 did not affect baseline renal parameters. However, because mean arterial pressure decreased, a tendency toward a reduction of renal vascular resistance could indeed be demonstrated. Compared with placebo, both doses of ABT-627 were equally effective in blocking all renal effects caused by ET-1 infusion. In the model of exogenous ET-1 infusion, ABT-627 had a tendency to prevent ET-1-induced renal changes more effectively compared with nifedipine. The contribution of endogenous ET-1 and the ET_A receptor in maintaining basal renal vascular tone in the human kidney is small. In addition, compared with placebo, selective ET_A receptor antagonism with both doses of ABT-627 completely prevented all renal changes caused by ET-1 infusion.

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Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673