Jpn. J. Pharmacol. 82 (4), 307-316 (2000)

Selective Antagonism of the ET_A Receptor, but Not the ET_B Receptor,
Is Protective Against Ischemic Acute Renal Failure in Rats

Toshihiko Kuro¹, Kaori Kohnou¹, Yutaka Kobayashi¹, Masanori Takaoka¹, Terry J. Opgenorth²,
Jerry L. Wessale² and Yasuo Matsumura^1,*


¹Departmentﾊof Pharmacology, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094, Japan
²Diabetesﾊand Vascular Research Division, Abbott Laboratories, Abbott Park, IL 60064-6123, USA
*ﾊTo whom correspondence should be addressed.

Abstract: We investigated the effects of ABT-627, a selective ET_A-receptor antagonist, and A-192621, a selective ET_B-receptor antagonist, on ischemic acute renal failure (ARF) in rats. Ischemic ARF was induced by clamping the left renal artery and vein for 45ﾊmin, 2ﾊweeks after the contralateral nephrectomy. Renal function in untreated ARF rats markedly decreased at 24ﾊh after reperfusion and thereafter tended to recover gradually. ABT-627 (1ﾊmg/kg,ﾊi.v.) administration before ischemia markedly attenuated the renal dysfunction induced by the ischemia/reperfusion, whereas A-192621 (3ﾊmg/kg,ﾊi.v.) pretreatment was without effect. Histopathological examination of the kidney of untreated ARF rats revealed severe renal damage such as tubular necrosis, proteinaceous casts in tubuli and medullary congestion. Histologically evident damage was improved by pre-treatment with ABT-627, but not with A-192621. Daily oral administratrion of ABT-627 (10ﾊmg/kg per day), but not A-192621 (30ﾊmg/kg per day), given after the ischemia/reperfusion period also exerted protective effects. These findings clearly indicate that endothelin, acting via the ET_A receptor, participates in the pathogenesis of ischemic ARF. Thus, selective ET_A-receptor antagonism may be useful in the treatment of human ischemic ARF, whereas selective blockade of the ET_B receptor will probably be ineffective.

Keywords: Endothelin-1, ET_A receptor, ET_B receptor, Acute renal failure, Renal function