Therapeutic administration of an endothelin-A receptor antagonist after acute ischemic renal failure dose-dependently improves recovery of renal function

Endothelin (ET) is known to reduce glomerular filtration rate and renal blo od flow and is a possible mediator of acute renal failure (ARF). We recentl y demonstrated that the administration of a very high dose of the ETA-recep tor antagonist LU 135252 (LU) accelerates recovery from postischemic acute renal failure by an improvement of renal perfusion in a rat model. The aim of this study was to investigate whether this effect of LU is dose dependen t. ARF was induced in rats by clamping both renal arteries. Serum creatinin e was measured and endogenous creatinine clearance and fractional sodium ex cretion were calculated up to 4 days after acute ischemia. Rats were treate d either with the selective ETA-receptor antagonist LU or with vehicle only after reperfusion. LU in doses of 0.5, 1, or 5 mg/kg per day was infused v ia a femoral vein using an osmotic minipump. Serum creatinine was increased approximately eightfold after induction of ARF. Creatinine clearance decre ased from 4.35 +/- 0.26 ml/min before acute renal failure to 0.15 +/- 0.02, 0.54 +/- 0.1, and 1.49 +/- 0.19 ml/min on days 1, 2, and 4 after ischemia (p < 0.05). Fractional sodium excretion increased from baseline 0.77 <plus/ minus> 0.05% to 7.5 +/- 1.21% on day 1 and 8.53 +/- 1.34% on day 2 (p < 0.0 5). Treatment with LU improved kidney function dose relatedly. There was no significant change in creatinine clearance, but compared with controls, wi th doses of 0.5 mg/kg per day and 1 mg/kg per day (0.28 <plus/minus> 0.1, 0 .88 +/- 0.22, and 1.93 +/- 0.24 ml/min on days 1, 2, and 4), we noted a sig nificant increase under 5 mg/kg per day (day 1: 0.62 +/- 0.17 ml/min; day 2 : 1.38 +/- 0.26 ml/min; and day 4: 2.45 +/- 0.21 ml/min; p < 0.05). Fractio nal sodium excretion decreased dose-relatedly to a maximally 2.48 <plus/min us> 0.58% on day 1 and 2.25 +/- 0.71% on day 2 after treatment with the hig hest dose when compared with untreated control rats (p < 0.05). Our data su pport the hypothesis that ET plays a major role in ARF. It can be concluded from these results that recovery from ischemic ARF is significantly and do se-dependently enhanced by treatment with a selective ETA-receptor antagoni st.