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 hypothesis that endothelin-1, the most potent renal vasoconstrictor known, plays a role in the renal toxicity of myoglobin. For this purpose, we induced 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 dramatically, increased proteinuria and induced a massive tubular necrosis. This effect was associated with a 22% increase in plasma endothelin concentration. Bosentan prevented the decrease in creatinine clearance (1.12 +/- 0.07 ml/min vs. 0.83 +/- 0.05 ml/min, P < .01), the increase 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 endothelin was further suggested by the observation that myoglobin could markedly increase endothelin-1 release by rat mesangial cells in culture. We conclude that endothelin is, at least in part, responsible for the massive tubular necrosis observed in myoglobinuric nephropathy.
Karam
H
H
Pharma Division, F. Hoffmann-La Roche Ltd., Basel, Switzerland.
Bruneval
P
P
Clozel
J P
JP
Löffler
B M
BM
Bariéty
J
J
Clozel
M
M
D058186:Acute Kidney Injury / Q000209:etiology / Q000503:physiopathology*; D000818:Animals; D000077300:Bosentan; D002478:Cells, Cultured; D016232:Endothelins / Q000097:blood / Q000502:physiology*; D005920:Glomerular Mesangium / Q000166:cytology / Q000378:metabolism; D007677:Kidney Function Tests; D008297:Male; D009212:Myoglobinuria / Q000150:complications / Q000652:urine; D051381:Rats; D017208:Rats, Wistar; D017466:Receptors, Endothelin / Q000187:drug effects; D012206:Rhabdomyolysis / Q000150:complications*; D013449:Sulfonamides / Q000494:pharmacology
D016232:Endothelins; D017466:Receptors, Endothelin; D013449:Sulfonamides; D000077300:Bosentan