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      Effect of Nitric Oxide on Ammoniagenesis in Rats

      research-article
      ,
      Nephron Physiology
      S. Karger AG
      Ammoniagenesis, Cyclosporin A, Nitric oxide, Permeability transition pore, Glutamine

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          Abstract

          Aim: This in vitro study using rat cortical slices, isolated proximal tubules and mitochondria was conducted to investigate the effect of exogenous and endogenous nitric oxide on ammoniagenesis. Methods and Results: The cortical slices were incubated with phosphate-buffered saline containing 1 m M L-glutamine at 37°C andglutamine-stimulated ammoniagenesis which was further elevated with 10<sup>–7</sup> M ANGII showed a time-dependent decrease during 2 h. 10<sup>–4</sup> M L-NAME or 10<sup>–5</sup> M L-canavanin caused a similar ammonia elevation to that of ANGII, whereas the addition of 10<sup>–5</sup> M SNAP attenuated the ammonia-increasing effects of ANGII and L-NAME. Basal or exogenous NO without significantly affecting glutamine uptake of the slices seemed to convert the glutamine deamidation pathway to transamination, since L-NAME increased the ammonia to glutamine ratio from 0.87 ± 0.08 mol/mol to 1.03 ± 0.04 (p < 0.01). L-NAME increased both ammoniagenesis and mitochondrial oxygen consumption but SNAP depressed them. Endogenous NO reduced ammoniagenesis without changing the mitochondrial permeability transition pore (PTP), whereas exogenous NO-induced attenuation in ammoniagenesis was associated with elevated PTP in a CsA-sensitive manner. Conclusion: These results demonstrated that in rat kidney, basal NO depresses mitochondrial oxygen consumption and attenuates ammoniagenesis without affecting PTP; however, exogenous NO inhibits ammonia production by disturbing PTP in isolated mitochondria.

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          Most cited references10

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          Glutamine and glutamate as vital metabolites

          Glucose is widely accepted as the primary nutrient for the maintenance and promotion of cell function. This metabolite leads to production of ATP, NADPH and precursors for the synthesis of macromolecules such as nucleic acids and phospholipids. We propose that, in addition to glucose, the 5-carbon amino acids glutamine and glutamate should be considered to be equally important for maintenance and promotion of cell function. The functions of glutamine/glutamate are many, i.e., they are substrates for protein synthesis, anabolic precursors for muscle growth, they regulate acid-base balance in the kidney, they are substrates for ureagenesis in the liver and for hepatic and renal gluconeogenesis, they act as an oxidative fuel for the intestine and cells of the immune system, provide inter-organ nitrogen transport, and act as precursors of neurotransmitter synthesis, of nucleotide and nucleic acid synthesis and of glutathione production. Many of these functions are interrelated with glucose metabolism. The specialized aspects of glutamine/glutamate metabolism of different glutamine-utilizing cells are discussed in the context of glucose requirements and cell function.
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            Biochemistry of mitochondrial nitric-oxide synthase.

            We reported that the generation of nitric oxide by mitochondria is catalyzed by a constitutive, mitochondrial nitric-oxide synthase (mtNOS). Given that this production may establish the basis for a novel regulatory pathway of energy metabolism, oxygen consumption, and oxygen free radical production, it becomes imperative to identify unequivocally and characterize this enzyme to provide a basis for its regulation. The mitochondrial localization of mtNOS was supported by following the hepatic distribution of mtNOS, immunoblotting submitochondrial fractions, and immunohistochemistry of liver tissues. mtNOS was identified as brain NOS alpha by various methods (mass spectrometry of proteolytic fragments, amino acid analysis, molecular weight, pI, and analysis of PCR fragments), excluding the occurrence of a novel isoform or other splice variants. Distribution of mtNOS transcript indicated its occurrence in liver, brain, heart, muscle, kidney, lung, testis, and spleen. In contrast to brain NOS, mtNOS has two post-translational modifications: acylation with myristic acid and phosphorylation at the C terminus. The former modification is a reversible and post-translational process, which may serve for subcellular targeting or membrane anchoring. The latter modification could be linked to enzymatic regulation. These results are discussed in terms of the role that nitric oxide may have in cellular bioenergetics.
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              Nitric oxide: the "second messenger" of insulin.

              Incubation of various tissues, including heart, liver, kidney, muscle, and intestine from mice and erythrocytes or their membrane fractions from humans, with physiologic concentration of insulin resulted in the activation of a membrane-bound nitric oxide synthase (NOS). Activation of NOS and synthesis of NO were stimulated by the binding of insulin to specific receptors on the cell surface. A Lineweaver-Burk plot of the enzymatic activity demonstrated that the stimulation of NOS by insulin was related to the decrease in the Km for L-arginine, the substrate for NOS, with a simultaneous increase of Vmax. Addition of NG-nitro-L-arginine methyl ester (LNAME), a competitive inhibitor of NOS, to the reaction mixture completely inhibited the hormone-stimulated NO synthesis in all tissues. Furthermore, NO had an insulin-like effect in stimulating glucose transport and glucose oxidation in muscle, a major site for insulin action. Addition of NAME to the reaction mixture completely blocked the stimulatory effect of insulin by inhibiting both NO production and glucose metabolism, without affecting the hormone-stimulated tyrosine or phosphatidyl-inositol 3-kinases of the membrane preparation. Injection of NO in alloxan-induced diabetic mice mimicked the effect of insulin in the control of hyperglycemia (i.e., lowered the glucose content in plasma). However, injection of NAME before the administration of insulin to diabetic-induced and nondiabetic mice inhibited not only the insulin-stimulated increase of NO in plasma but also the glucose-lowering effect of insulin.
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                Author and article information

                Journal
                NEP
                Nephron Physiol
                10.1159/issn.1660-2137
                Nephron Physiology
                S. Karger AG
                1660-2137
                2006
                February 2006
                23 February 2006
                : 102
                : 3-4
                : p61-p71
                Affiliations
                Akdeniz University, Faculty of Medicine, Department of Physiology, Antalya,Turkey
                Article
                89683 Nephron Physiol 2006;102:p61–p71
                10.1159/000089683
                16286788
                acb2f4d7-e716-4333-9361-e11adce670d2
                © 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.

                History
                : 14 September 2004
                : 06 August 2005
                Page count
                Figures: 4, Tables: 3, References: 38, Pages: 1
                Categories
                Original Paper

                Cardiovascular Medicine,Nephrology
                Ammoniagenesis,Glutamine,Permeability transition pore,Nitric oxide,Cyclosporin A

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