a-192621 and Reperfusion-Injury

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.

Topics: Acute Kidney Injury; Animals; Atrasentan; Endothelin Receptor Antagonists; Endothelin-1; Ischemia; Kidney; Male; Pyrrolidines; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin; Reperfusion Injury

The role of specific endothelin receptors in the early renal reperfusion and long-term survival in renal transplantation was investigated in Lewis rats. Left renal transplantation was performed following 2 h cold ischaemia without and with ET(A) receptor antagonism and following 16 h cold ischaemia with no treatment, with ET(A) receptor antagonism and with ET(B) receptor antagonism. The ET(A) and ET(B) receptor antagonists, BQ-610 and A-192621 respectively, were added to the preservation solution. Renal cortical perfusion (RCP) was measured postoperatively using laser Doppler flowmetry. All rats in the 2-hour groups survived for 15 days. Animals in the untreated 16-hour group or in the A-192621-treated group died between days 3 and 6 after surgery. Fifty percent of the rats in the 16-hour and BQ-610-treated group died between days 4 and 7 after surgery while the other 50% survived for 15 days. Survival rates correlated well with both the postoperative serum creatinine and the recovery of RCP. We conclude that addition of an ET(A) receptor antagonist to the preservation solution improves renal reperfusion and long-term survival following prolonged ischaemia, whereas ET(B) receptor antagonism does neither.

Topics: Animals; Cold Temperature; Endothelin Receptor Antagonists; Endothelin-1; Kidney Cortex; Kidney Transplantation; Male; Oligopeptides; Organ Preservation; Pyrrolidines; Rats; Rats, Inbred Lew; Receptor, Endothelin A; Receptor, Endothelin B; Reperfusion Injury