ROLE OF ENDOTHELIN IN ACUTE-RENAL-FAILURE DUE TO RHABDOMYOLYSIS IN RATS

Rhabdomyolysis and other causes of massive myoglobin release are often complicated by an acute ischemic renal failure. We tested the hypothe sis that endothelin-1, the most potent renal vasoconstrictor known, pl ays a role in the renal toxicity of myoglobin. For this purpose, we in duced rhabdomyolysis (8 ml/kg i.m. of a 50% glycerol solution) in rats pretreated or not pretreated with bosentan, a novel potent nonpeptide endothelin receptor antagonist. Glycerol decreased renal function dra matically, increased proteinuria and induced a massive tubular necrosi s. This effect was associated with a 22% increase in plasma endothelin concentration. Bosentan prevented the decrease in creatinine clearanc e (1.12 +/- 0.07 ml/min vs. 0.83 +/- 0.05 ml/min, P < .01), the increa se in proteinuria (19.9 mg/24 hr vs. 31.8 mg/24 hr, P < .001) and the tubular necrosis induced by glycerol (as assessed by histopathological evaluation), without affecting myoglobinuria. Involvement of endothel in was further suggested by the observation that myoglobin could marke dly increase endothelin-1 release by rat mesangial cells in culture. W e conclude that endothelin is, at least in part, responsible for the m assive tubular necrosis observed in myoglobinuric nephropathy.