NONPEPTIDE ENDOTHELIN RECEPTOR ANTAGONISTS .3. EFFECT OF SB-209670 AND BQ123 ON ACUTE-RENAL-FAILURE IN ANESTHETIZED DOGS

Endothelin (ET) is a potent vasoconstrictor that has been implicated i n the pathogenesis of acute renal failure (ARF). In order to investiga te the potential role of ET in ARF in the dog, the effect of a mixed E T(A) and ET(B) receptor antagonist, (+/-)-SB 209670, [(1RS-2SR,3RS)-3- (2-carboxymethoxy-4-methoxy- phenyl)-5-(prop-1-yloxy)indane-2-carboxyl ic acid], and a selective ET(A) antagonist, BQ123, were evaluated in a nesthetized uninephrectomized dogs undergoing 60 min of renal occlusio n. (+/-)-SB 209670 (1 mu g/kg/min) and BQ123 (10 mu g/kg/min) were inf used directly into the renal artery (intrarenal) for 30 min before ren al occlusion, during occlusion and for 60 min after reperfusion at dos es that inhibited the renal vasoconstrictor effects of intrarenal rena l artery infusions of ET-1. Renal occlusion resulted in a significant reduction in inulin clearance (from 26.2 +/- 1.8 to 3.2 +/- 1.1 ml/min ). This response was significantly (P < .05) attenuated by (+/-)-SB 20 9670 (from 23.5 +/- 2.2 to 7.6 +/- 2.0 ml/min) but not by BQ123 (from 23.5 +/- 1.7 to 4.9 +/- 1.2 ml/min). Endogenous creatinine clearance s howed the same pattern. After renal artery occlusion, fractional sodiu m and fractional potassium excretions were increased significantly. (/-)-SB 209670, but not BQ123, resulted in a significant reduction in f ractional sodium; however, neither compound altered fractional potassi um excretion. The data suggest that ET receptor antagonists, possibly by altering tubular sodium reabsorption, may be beneficial in ischemia -induced ARF.