Protective effect of SM-19712, a novel and potent endothelin converting enzyme inhibitor, on ischemic acute renal failure in rats.
Effects of SM-19712 (4-chloro-N-[[(4-cyano-3-methyl- 1-1-phenyl- 1H-pyrazol-5-yl)amino]carbonyl] benzenesulfonamide, monosodium salt), a novel endothelin converting enzyme (ECE) inhibitor, on ischemic acute renal failure (ARF) in rats were examined in comparison with those of phosphoramidon, a conventional ECE inhibitor. ARF was induced by occlusion of the left renal artery and vein for 45 min followed by reperfusion, 2 weeks after contralateral nephrectomy. Renal function in ARF rats markedly decreased at 24 h after reperfusion. Intravenous bolus injection of SM-19712 (3, 10, 30 mg/kg) prior to the occlusion attenuated dose-dependently the ischemia/reperfusion-induced renal dysfunction. Histopathological examination of the kidney of ARF rats revealed severe renal damages such as tubular necrosis, proteinaceous casts in tubuli and medullary congestion, all of which were dose-dependently attenuated by SM-19712. Protective effects of phosphoramidon (10 mg/kg) on ARF-induced functional and tissue damages were less potent than that of the same dose of SM-19712. Endothelin-1 (ET-1) content in the kidney after the ischemia/reperfusion was significantly increased, being the maximum level at 6 h after reperfusion, and this elevation was completely suppressed by the higher dose of SM-19712. Our findings support the view that renal ET-1 plays an important role in the development of ischemia/reperfusion-induced renal injury. SM-19712 may be useful in the treatment of ischemic ARF.
Matsumura
Y
Y
Department of Pharmacology, Osaka University of Pharmaceutical Sciences, Nasahara, Takatsuki, Japan.
Kuro
T
T
Kobayashi
Y
Y
Umekawa
K
K
Ohashi
N
N
Takaoka
M
M
D058186:Acute Kidney Injury / Q000097:blood / Q000473:pathology / Q000517:prevention & control*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019332:Endothelin-1 / Q000097:blood / Q000378:metabolism; D000072396:Endothelin-Converting Enzymes; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006020:Glycopeptides / Q000627:therapeutic use; D007511:Ischemia / Q000473:pathology / Q000517:prevention & control*; D007677:Kidney Function Tests; D008297:Male; D008666:Metalloendopeptidases; D020011:Protective Agents / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000627:therapeutic use*; D013453:Sulfonylurea Compounds / Q000627:therapeutic use*
D019332:Endothelin-1; D004791:Enzyme Inhibitors; D006020:Glycopeptides; D020011:Protective Agents; C419789:SM 19712; D013449:Sulfonamides; D013453:Sulfonylurea Compounds; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; D000072396:Endothelin-Converting Enzymes; C008890:phosphoramidon