Y. Matsumura et al., Protective effect of SM-19712, a novel and potent endothelin converting enzyme inhibitor, on ischemic acute renal failure in rats, JPN J PHARM, 84(1), 2000, pp. 16-24
Effects of SM-19712 (4-chloro-N-[[(4-cyano-3-methyl-1-phenyl-1H-pyrazol-5-y
l)amino] carbonyl] benzenesulfonamide, monosodium salt), a novel endothelin
converting enzyme (ECE) inhibitor, on ischemic acute renal failure (ARF) i
n rats were examined in comparison with those of phosphoramidon, a conventi
onal ECE inhibitor. ARF was induced by occlusion of the left renal artery a
nd vein for 45 min followed by reperfusion, 2 weeks after contralateral nep
hrectomy. Renal function in ARF rats markedly decreased at 24 h after reper
fusion. 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 att
enuated by SM-19712. Protective effects of phosphoramidon (10 mg/kg) on ARF
-induced functional and tissue damages were less potent than that of the sa
me dose of SM-19712. Endothelin-l (ET-I) content in the kidney after the is
chemia/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 play
s an important role in the development of ischemia/reperfusion-induced rena
l injury. SM-19712 may be useful in the treatment of ischemic ARF.