Effect of an endothelin-receptor antagonist on ischemic acute renal failure

Chan, L.; Chittinandana, A.; Shapiro, J.I.; Shanley, P.F.; Schrier, R.W.

American Journal of Physiology 266(1 Pt 2): F135-F138

1994


ISSN/ISBN: 0002-9513
PMID: 8304480
Accession: 008523164

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Abstract
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 cntdot min-1 cntdot g-1; P lt 0.01 compared with control) and C-In (89 +- 13 vs. 317 +- 19 mu-l cntdot min-1 cntdot g1-1; P lt 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 cntdot min-1 cntdot g-1; not significant (NS) compared with control) and C-In (299 +- 51 vs. 317 +- 19 mu-l cntdot min-1 cntdot 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 cntdot min-1 cntdot g-1; NS compared with control) or C-In. (320 +- 14 vs. 317 +- 19 mu-l cntdot min-1 cntdot 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 cntdot min-1 cntdot g-1; n = 6, P lt 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 cntdot kg-1 cntdot 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/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.