Role of endothelin in acute renal failure due to rhabdomyolysis in rats

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 274; no. 1; pp. 481 - 486
• Main Authors: Karam, H, Bruneval, P, Clozel, J P, Löffler, B M, Bariéty, J, Clozel, M
• Format: Journal Article
• Language: English
• Published: United States American Society for Pharmacology and Experimental Therapeutics 01.07.1995
• Subjects: Acute Kidney Injury - etiology; Acute Kidney Injury - physiopathology; Animals; Cells, Cultured; Endothelins - blood; Endothelins - physiology; Glomerular Mesangium - cytology; Glomerular Mesangium - metabolism; Kidney Function Tests; Male; Myoglobinuria - complications; Myoglobinuria - urine; Rats; Rats, Wistar; Receptors, Endothelin - drug effects; Rhabdomyolysis - complications; Sulfonamides - pharmacology
• ISSN: 0022-3565; 1521-0103

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.