EFFECT OF AN ENDOTHELIN-RECEPTOR ANTAGONIST ON ISCHEMIC ACUTE-RENAL-FAILURE

In the isolated perfused rat kidney, endothelin (ET) added to the perfusate at concentrations ranging from 50 to 500 pmol/l resulted in a dose-dependent reduction in renal perfusate flow (RPF) and inulin clearance (C-In). The decrease in RPF (17 +/- 3 vs. 34 +/- 3 ml.min(-1).g(-1); P < 0.01 compared with control) and C-In (89 +/- 13 vs. 317 +/- 19 mu l.min(-1).g(-1); P < 0.01 compared with control) by ET (500 pmol/l) was prevented by the ET antagonist BQ-123 (10 mu M), with full recovery of RPF [36 +/- 2 vs. 34 +/- 3 ml.min(-1).g(-1); not significant (NS) compared with control] and C-In (299 +/- 51 vs. 317 +/- 19 mu L.min(-1).g(-1); NS compared with control). In the absence of ET, perfusion of the kidney with a similar concentration of BQ-123 (10 mu M) did not induce any changes in RPF (36 +/- 5 vs. 34 +/- 3 ml.min(-1).g(-1); NS compared with control) or C-IN (320 +/- 14 vs. 317 +/- 19 mu l.min(-1).g(-1); NS compared with control). After 60 min of arterial clamping, BQ-123 (10 mu M) given before the onset of ischemia and during reflow improved C-IN (88 +/- 4 vs. 19 +/- 3 mu l.min(-1).g(-1); n = 6, P < 0.01) and net tubular sodium reabsorption (T-Na) compared with no treatment. On the other hand, the same dose (10 mu M) of BQ-123 given only during the reperfusion period was not effective in preventing the decreases in either C-In or T-Na. Further studies were then performed to study the in vivo effect of BQ-123 in ischemic acute renal failure. Renal ischemia was induced by bilateral renal artery clamp for 45 min. BQ-123 (0.5 mg.kg(-1) min(-1) iv) or vehicle was infused both 30 min before clamping and during the 60-min reperfusion period. Treatment with BQ-123 resulted in significantly better C-In (1,310 +/- 50 vs. 590 +/- 85 mu l.min at 2 h; 1,920 +/- 160 vs. 810 +/- 90 mu l/min at 48 h of reflow) and T-Na (175 +/- 15 vs. 80 +/- 10 mu l/min at 2 h; 270 +/- 15 vs. 110 +/- 10 mu l/min at 48 h of reflow) compared with vehicle. The effect of BQ-123 on the severity of injury in the S3 segment of the proximal tubule 48 h after ischemia was also found to be significantly less in the treated group. These results therefore suggest that BQ-123, the ET-receptor antagonist, is potentially an important agent in the prevention of ischemic acute renal failure.