Selective antagonism of the ETA receptor, but not the ETB receptor, is protective against ischemic acute renal failure in rats

We investigated the effects of ABT-627, a selective ETA-receptor antagonist , and A-192621, a selective ETB-receptor antagonist, on ischemic acute rena l failure (ARF) in rats. Ischemic ARF was induced by clamping the left rena l artery and vein for 45 min, 2 weeks after the contralateral nephrectomy. Renal function in untreated ARF rats markedly decreased at 24 h after reper fusion and thereafter tended to recover gradually. ABT-627 (1 mg/kg, i.v.) administration before ischemia markedly attenuated the renal dysfunction in duced by the ischemia/reperfusion, whereas A-192621 (3 mg/kg, i.v.) pretrea tment was without effect. Histopathological examination of the kidney of un treated ARF rats revealed severe renal damage such as tubular necrosis, pro teinaceous casts in tubuli and medullary congestion. Histologically evident damage was improved by pretreatment with ABT-627, but not with A-192621. D aily oral administration of ABT-627 (10 mg/kg per day), but not A-192621 (3 0 mg/kg per day), given after the ischemia/reperfusion period also exerted protective effects. These findings clearly indicate that endothelin, acting via the ETA receptor, participates in the pathogenesis of ischemic ARF. Th us, selective ETA-receptor antagonism may be useful in the treatment of hum an ischemic ARF, whereas selective blockade of the ETB receptor will probab ly be ineffective.