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−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.