IMPROVEMENT OF POSTISCHEMIC ACUTE-RENAL-FAILURE WITH THE NOVEL ORALLY-ACTIVE ENDOTHELIN-A RECEPTOR ANTAGONIST LU-135252 IN THE RAT

The endothelin (ET) system may play an important role in the pathogene sis of acute renal failure (ARF). We hypothesize that the course of AR F in an ischemia-reperfusion model will be markedly attenuated by the orally active ETA-receptor antagonist LU 135252 (LU) because of an imp rovement of renal perfusion. ARF was induced in rats by clamping both renal arteries for 60 min. The study was divided into two parts. In pa rt 1, Rats received LU orally (100 mg/kg/day) starting 1 h after induc tion of ARF for 14 days. Cr-s, Cl-cr and FEna were measured on days 1, 6, 9, and 14 after ARF. Cr-s was lower in the treatment group on days 1 [1.3 +/- 0.31 mg/dl (n = 9) vs. 2.71 +/- 0.46 mg/dl (n = 10); p < 0 .05] and 6 [0.5 +/- 0.1 mg/dl (n = 9) vs. 1.0 +/- 0.2 mg/dl (n = 9), p < 0.05], and Cl-cr was higher on day 1 [0.9 +/- 0.17 ml/min (n = 9) v s. 0.2 +/- 0.1 ml/min (n = 8), p < 0.05] and 6 [1.8 +/- 0.29) ml/min ( n = 9) vs. 1.0 +/- 0.21 ml/min (n = 9); p < 0.05] compared with vehicl e. Additionally, FEna was lower in treated rats on day 1 [1 +/- 0.4% ( n = 9) vs. 8 +/- 3% (n = 8); p < 0.05] compared with vehicle. In part 2, ARF was induced as described. Treated animals received 10 mg/kg LU on days 0, 1, 3, 6, 9, and 14 after ARF as an i.v. bolus injection. RB E cortex blood flow (CBF), and medulla blood flow (MBF) were measured after application of LU on the same days: LU induced an increase in RB F (day 1: 14 +/- 5.3%, n = 6, p = 0.04: day 3: 15 +/- 2.8%, n = 8, p = 0.0008; day 6: 21 +/- 5.8%, n = 6, p = 0.0.02; day 9: 13 +/- 4%, n = 6; p = 0.03) and CBF (day 1: 8 +/- 2.2%, n = 7, p = 0.03; day 3: 7 +/- 2.5%, n = 7: p = 0.05: day 6: 18 +/- 4.8%, n = 6, p = 0.04; day 9: 10 +/- 2.5%, n = 6; p = 0.008) up to the first 9 days. MBF did increase on days 1 (9 +/- 3.1%, n = 6; p = 0.04) and 6 (13 +/- 3.6%, n = 6; p = 0.03). Our data confirm the hypothesis that ET plays a major role in the genesis of ARF associated with ischemia-reperfusion.