Effects of Co-Administration of an iNOS Inhibitor with a Broad-Spectrum Reactive Species Scavenger in Rat Renal Ischemia/Reperfusion Injury

Abstract

Background: It is generally believed that reactive oxygen species (ROS) formation and nitric oxide (NO) generation by the inducible isoform of nitric oxide synthase (iNOS) are the key mediators of ischemia-reperfusion (IR)-induced damage to the kidney. The present study was designed to investigate the effects of ROS and NOS inhibition in prevention of renal IR injury. MnTBAP (Manganese (III) meso-tetrakis (4-benzoic acid) porphyrin), a broad-spectrum reactive species scavenger was administered to inhibit ROS formation and L-Nil (N6-(1-iminoethyl)- L-lysine hydrochloride) was used for iNOS inhibition. Methods: Ischemic acute renal failure (ARF) was induced by 40-min clamping of the renal arteries followed by a 6-hour reperfusion. Rats were administered saline, MnTBAP (10 mg/kg i.v.), L-Nil (3 mg/kg i.v. bolus followed by infusion of 1 mg/kg/h) or co-administration of MnTBAP and L-Nil. Plasma creatinine (Cr) and BUN levels as well as fractional excretion of Na⁺ (FE_Na+) and urinary N-acetyl-β- D-glucosaminidase (NAG) activities were measured. Renal damages were evaluated by light microscopy. Results: MnTBAP, L-Nil and their co-administration significantly improved renal functional and histological indices. Co-administration of the mentioned drugs did not demonstrate significant difference with the administration of either drug alone. Conclusion: These results suggest that the significant portion of ROS and iNOS nephrotoxicities in this model of ARF may be mediated by peroxynitrite (ONOO^–). These results emphasize the multifactorial nature of ARF and the need for a multidrug therapy in the future.