title: Role of endothelin in acute renal failure due to rhabdomyolysis in rats.
abstract: 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.
authors.affiliation: Pharma Division, F. Hoffmann-La Roche Ltd., Basel, Switzerland.
authors.forename: H
authors.initials: H
authors.lastname: Karam
authors.forename: P
authors.initials: P
authors.lastname: Bruneval
authors.forename: J P
authors.initials: JP
authors.lastname: Clozel
authors.forename: B M
authors.initials: BM
authors.lastname: Löffler
authors.forename: J
authors.initials: J
authors.lastname: Bariéty
authors.forename: M
authors.initials: M
authors.lastname: Clozel
mesh_terms: 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
chemical_list: D016232:Endothelins; D017466:Receptors, Endothelin; D013449:Sulfonamides; D000077300:Bosentan