Effects of co-administration of an iNOS inhibitor with a broad-spectrum reactive species scavenger in rat renal ischemia/reperfusion injury.
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-beta-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.


CONCLUSIONS
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.
Zahmatkesh
M
M
Department of Physiology, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
Kadkhodaee
M
M
Arab
H A
HA
Shams
S
S
D000818:Animals; D004338:Drug Combinations; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D016166:Free Radical Scavengers / Q000494:pharmacology*; D005978:Glutathione / Q000172:deficiency; D007668:Kidney / Q000098:blood supply* / Q000473:pathology; D007678:Kidney Glomerulus / Q000187:drug effects / Q000503:physiopathology; D007684:Kidney Tubules / Q000187:drug effects / Q000503:physiopathology; D008239:Lysine / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D008665:Metalloporphyrins / Q000494:pharmacology; D009566:Nitrates / Q000097:blood; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors*; D009573:Nitrites / Q000097:blood; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology*
D004338:Drug Combinations; D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D008665:Metalloporphyrins; C090663:N(6)-(1-iminoethyl)lysine; D009566:Nitrates; D009573:Nitrites; C097284:manganese(III)-tetrakis(4-benzoic acid)porphyrin; D052247:Nitric Oxide Synthase Type II; D005978:Glutathione; D008239:Lysine