Vol. 287, Issue 3, 1084-1091, December 1998

Protective Effect of FK409, a Spontaneous Nitric Oxide Releaser, on Ischemic Acute Renal Failure in Rats

Yasuo Matsumura, Manabu Nishiura, Shougo Deguchi, Norio Hashimoto, Toshikazu Ogawa and Rumi Seo

Department of Pharmacology (Y. M., M. N., S. D., N. H., R. S.), Osaka University of Pharmaceutical Sciences, Nasahara, Takatsuki, Osaka 569-1094, Japan; Medical Biology Research Laboratory (T. O.), Fujisawa Pharmaceutical Co., Ltd.; and Kashima, Yodogawa-ku, Osaka 532-0031, Japan

The contribution of nitric oxide (NO) to ischemic acute renal failure (ARF) is controversial. In the present study, we investigated the effect of FK409 ((±)-(E)-4-ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexanamide), a spontaneous NO donor, on ischemic ARF in rats. Ischemic ARF was induced by occlusion of the left renal artery and vein for 45 min followed by reperfusion, 2 weeks after contralateral nephrectomy. Renal functional parameters such as blood urea nitrogen, plasma creatinine, creatinine clearance, urine flow, urinary osmolality and fractional excretion of sodium were measured to test the effectiveness of the drug. Renal function in untreated ARF rats markedly decreased at 24 hr after reperfusion and thereafter tended to recover gradually. Intravenous bolus injection of FK409 at a dose of 1 mg/kg before the occlusion markedly attenuated the ischemic ARF-induced decreases in renal function, to the same extent as verapamil (1 mg/kg i.v.). The protective effect of FK409, at a dose of 3 mg/kg, was much more potent than that of the lower dose. Histopathological examination of the kidney of untreated ARF rats revealed severe renal damages, such as tubular necrosis, proteinaceous casts in tubuli and medullary congestion. These renal damages were significantly attenuated by treatment with FK409, at each dose given and this attenuation exceeded that seen with verapamil treatment. FK 409 administration led to a dose-dependent increase in NO metabolites concentration in renal venous blood immediately after the reperfusion. These findings suggest that NO has a crucial role in the pathogenesis of ischemic ARF. Spontaneous NO donors may be clinically effective in cases of ischemic ARF.