Jpn. J. Pharmacol. 84 (1), 16-24 (2000)
Protective Effect of SM-19712, a Novel and Potent Endothelin Converting
Enzyme Inhibitor, on Ischemic Acute Renal Failure in Rats
Yasuo Matsumura1, Toshihiko Kuro1, Yutaka Kobayashi1,
Kayo Umekawa2, Naohito Ohashi2 and Masanori Takaoka1
1Departmentﾊof Pharmacology, Osaka University of Pharmaceutical
Sciences, Nasahara, Takatsuki, Osaka 569-1094, Japan
2ResearchﾊCenter, Sumitomo Pharmaceuticals Co., Ltd., Osaka 554-0022,
Japan
Abstract: 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ﾊmin followed by reperfusion, 2ﾊweeks after contralateral nephrectomy.
Renal function in ARF rats markedly decreased at 24ﾊh after reperfusion.
Intravenous bolus injection of SM-19712 (3, 10, 30ﾊ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ﾊ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ﾊ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.
Keywords: Endothelin-1, Endothelin converting enzyme, Ischemia, Acute
renal failure, Renal function
Copyrightｩ The Japanese Pharmacological Society 2000
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