NONPEPTIDE ENDOTHELIN RECEPTOR ANTAGONISTS .5. PREVENTION AND REVERSAL OF ACUTE-RENAL-FAILURE IN THE RAT BY SB-209670

The ability of the mixed endothelin (ET(A)/ET(B)) receptor antagonist (+/-)-SB 209670 to prevent and reverse ischemia-induced acute renal fa ilure (ARF) was studied in rats with moderate and severe ARF. Uninephr ectomized, chronically instrumented Sprague-Dawley rats were used. Mod erate and severe ARF was induced by occlusion of the renal artery for 30 and 45 min, respectively. During the 24 hr after 30-min ischemia (m oderate ARF), glomerular filtration rate (GFR) decreased by 95%, and f ractional excretion of sodium increased from 0.6% to 10%. infusion of (+/-)-SB 209670 at 10, 30 and 100 mu g/kg min for 30 min before, durin g and 60 min after renal ischemia had a moderate effect on renal funct ion. Thus, with the highest dose, the ischemia-induced reduction in GF R was 70%. This dose, however, had no effect in rats when given before , during and after 45 min of renal ischemia (severe ARF). In contrast, when infused at 30 mu g/kg min for 3 hr on the day after ischemia, (/-)-SB 209670 markedly increased survival rate (75%) in rats with seve re ARF by significantly increasing tubular reabsorption of Na+, follow ed by a slow and gradual increase in GFR and reversal bf the increase in plasma K+ concentration. Data from acute renal clearance studies in rats with moderate ARF showed that when infused 24 hr after ischemia, (+)-SB 209670 acutely reversed the impairment in sodium reabsorption without increasing GFR or renal blood flow. These data indicate that t he negative effects of endothelin are expressed mainly during the main tenance phase of ARF; thus, ET receptor antagonists may be more effect ive in reversing than in preventing renal impairment after ischemia.