REVERSAL OF POSTISCHEMIC ACUTE-RENAL-FAILURE WITH A SELECTIVE ENDOTHELIN(A) RECEPTOR ANTAGONIST IN THE RAT

Studies were designed to examine the effect of a selective endothelin( A) (ET(A)) receptor antagonist, BQ123, on severe postischemic acute re nal failure (ARF) in Sprague-Dawley rats. Severe ARF was induced in un inephectomized, chronically instrumented rats by 45-min renal artery o cclusion. BQ123 (0.1 mg/kg.min) or vehicle was infused intravenously f or 3 h on the day after ischemia. Measurements before infusion (24 h c ontrol) showed a 98% decrease in glomerular filtration rate (GFR), inc rease in fractional excretion of sodium from 0.6 to 39%, and in plasma K+ from 4.3 to 6.5 mEq/liter. All vehicle-treated rats died in 4 d be cause of continuous deterioration of renal function, resulting in an i ncrease of plasma K+ to fatal levels (> 8 mEq/liter). Infusion of BQ12 3 significantly improved survival rate (75%) by markedly improving tub ular reabsorption of Na+ and moderately increasing GFR and K+ excretio n. Plasma K+ returned to basal levels by the 5th d after ischemia. Imp roved tubular function was followed by gradual recovery in GFR and uri nary concentrating mechanism. Additional data from renal clearance stu dies in rats with moderate ARF (30-min ischemia) and in normal rats wi th intact kidneys showed that ET(A) receptor blockade increases Na+ re absorption and has no effect on renal hemodynamics. These results indi cate that in the rat, the ET(A) receptor subtype mediates tubular epit helial function, and it plays a significant role in the pathogenesis o f ischemia-induced ARF. Treatment with the selective ET(A) receptor an tagonist reverses deteriorating tubular function in established ARF, a n effect of possible therapeutic significance.