We investigated the effects of
ABT-627, a selective ETA-receptor antagonist, and
A-192621, a selective ETB-receptor antagonist, on ischemic
acute renal failure (ARF) in rats. Ischemic ARF was induced by clamping the left renal artery and vein for 45 min, 2 weeks after the contralateral
nephrectomy. Renal function in untreated ARF rats markedly decreased at 24 h after reperfusion and thereafter tended to recover gradually.
ABT-627 (1 mg/kg, i.v.) administration before
ischemia markedly attenuated the renal dysfunction induced by the
ischemia/reperfusion, whereas
A-192621 (3 mg/kg, 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 pretreatment with
ABT-627, but not with
A-192621. Daily
oral administration of
ABT-627 (10 mg/kg per day), but not
A-192621 (30 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. Thus, selective ETA-receptor antagonism may be useful in the treatment of human ischemic ARF, whereas selective blockade of the ETB receptor will probably be ineffective.