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

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          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<sup>+</sup> (FE<sub>Na+</sub>) 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<sup>–</sup>). These results emphasize the multifactorial nature of ARF and the need for a multidrug therapy in the future.

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          Most cited references 19

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          Biochemistry of nitric oxide and its redox-activated forms

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            Reactive oxygen species and acute renal failure.

            Acute renal failure is commonly due to acute tubular necrosis (ATN), the latter representing an acute, usually reversible loss of renal function incurred from ischemic or nephrotoxic insults occurring singly or in combination. Such insults instigate a number of processes-hemodynamic alterations, aberrant vascular responses, sublethal and lethal cell damage, inflammatory responses, and nephron obstruction-that initiate and maintain ATN. Eventually, reparative and regenerative processes facilitate the resolution of renal injury and the recovery of renal function. Focusing mainly on ischemic ATN, this article reviews evidence indicating that the inordinate or aberrant generation of reactive oxygen species (ROS) may contribute to the initiation and maintenance of ATN. This review also discusses the possibility that ROS may instigate adaptive as well as maladaptive responses in the kidney with ATN, and raises the possibility that ROS may participate in the recovery phase of ATN.
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              Manganic porphyrins possess catalase activity and protect endothelial cells against hydrogen peroxide-mediated injury.

              Manganic porphyrins are redox active metal complexes that have been employed as superoxide dismutase mimics. We tested whether these metalloporphyrins could also dismute hydrogen peroxide (H2O2) and whether they could protect endothelial cells against H2O2. Both of the manganic metalloporphyrins tested were found to catalytically dismute H2O2. These manganic porphyrins also protected endothelial cells in dose-dependent manners against H2O2-mediated injury with MnTMPyP having an EC50 of 8 microM and MnTBAP having an EC50 of 15 microM. The zinc containing analogs of these porphyrins were inactive in dismuting H2O2 and did not protect. These studies further define the antioxidant capacity of metalloporphyrins in converting superoxide to H2O2 and H2O2 to water. These data suggest that manganic porphyrins may be useful therapeutics against disease states associated with the overproduction of reactive oxygen species. Copyright 1997 Academic Press.
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                Author and article information

                Journal
                NEE
                Nephron Exp Nephrol
                10.1159/issn.1660-2129
                Cardiorenal Medicine
                S. Karger AG
                1660-2129
                2006
                June 2006
                22 March 2006
                : 103
                : 3
                : e119-e125
                Affiliations
                aDepartment of Physiology, Faculty of Medicine, Tehran University of Medical Sciences, bDepartment of Physiology and Pharmacology, Faculty of Veterinary Medicine, Tehran University, and cChildren’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran
                Article
                92197 Nephron Exp Nephrol 2006;103:e119–e125
                10.1159/000092197
                16554662
                © 2006 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                Figures: 4, References: 27, Pages: 1
                Product
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/92197
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