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      Pyruvate in the Correction of Intracellular Acidosis: A Metabolic Basis as a Novel Superior Buffer

      American Journal of Nephrology

      S. Karger AG

      Pyruvate, Lactate, Bicarbonate, Glucose, Ischemia, Intracellular pH, Acidosis

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          Abstract

          The review focuses on biochemical metabolisms of conventional buffers and emphasizes advantages of sodium pyruvate (Pyr) in the correction of intracellular acidosis. Exogenous lactate (Lac) as an alternative of natural buffer, bicarbonate, consumes intracellular protons on an equimolar basis, regenerating bicarbonate anions in plasma while the completion of gluconeogenesis and/or oxidation occurs via tricarboxylic-acid cycle in mitochondria mainly in liver and kidney, or heart. The general assumption that Lac is ‘metabolized to bicarbonate’ in liver to serve as a buffer has been questioned. Pyr as a novel buffer would be superior to conventional ones in the correction of metabolic acidosis. Several likely biochemical mechanisms of Pyr action are discussed. Experimental evidence, in vivo, strongly suggested that Pyr would be particularly efficient in the correction of severe acidemia: type A lactic acidosis, hypercapnia with cardiac arrest, and diabetic and alcoholic ketoacidosis in animal experiments and clinic settings. Because of its multi-cytoprotection, Pyrs not only correct acidosis, but also benefit theunderlying dysfunction of vital organs. In addition, Pyr is also a potential buffer component of dialysis solutions. However, the instability of Pyr in aqueous solutions restricts its clinical applications as a therapeutic agent. Attempts to create a stable Pyr preparation are needed.

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          Most cited references 35

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          Hypoxia and acidosis activate cardiac myocyte death through the Bcl-2 family protein BNIP3.

          Coronary artery disease leads to injury and loss of myocardial tissue by deprivation of blood flow (ischemia) and is a major underlying cause of heart failure. Prolonged ischemia causes necrosis and apoptosis of cardiac myocytes and vascular cells; however, the mechanisms of ischemia-mediated cell death are poorly understood. Ischemia is associated with both hypoxia and acidosis due to increased glycolysis and lactic acid production. We recently reported that hypoxia does not induce cardiac myocyte apoptosis in the absence of acidosis. We now report that hypoxia-acidosis-associated cell death is mediated by BNIP3, a member of the Bcl-2 family of apoptosis-regulating proteins. Chronic hypoxia induced the expression and accumulation of BNIP3 mRNA and protein in cardiac myocytes, but acidosis was required to activate the death pathway. Acidosis stabilized BNIP3 protein and increased the association with mitochondria. Cell death by hypoxia-acidosis was blocked by pretreatment with antisense BNIP3 oligonucleotides. The pathway included extensive DNA fragmentation and opening of the mitochondrial permeability transition pore, but no apparent caspase activation. Overexpression of wild-type BNIP3, but not a translocation-defective mutant, activated cardiac myocyte death only when the myocytes were acidic. This pathway may figure significantly in muscle loss during myocardial ischemia.
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            A controlled clinical trial of dichloroacetate for treatment of lactic acidosis in adults. The Dichloroacetate-Lactic Acidosis Study Group.

            Mortality is very high in lactic acidosis, and there is no satisfactory treatment other than treatment of the underlying cause. Uncontrolled studies have suggested that dichloroacetate, which stimulates the oxidation of lactate to acetyl-coenzyme A and carbon dioxide, might reduce morbidity and improve survival among patients with this condition. We conducted a placebo-controlled, randomized trial of intravenous sodium dichloroacetate therapy in 252 patients with lactic acidosis; 126 were assigned to receive dichloroacetate and 126 to receive placebo. The entry criteria included an arterial-blood lactate concentration of > or = 5.0 mmol per liter and either an arterial-blood pH of or = 6 mmol per liter. The mean (+/- SD) arterial-blood lactate concentrations before treatment were 11.6 +/- 7.0 mmol per liter in the dichloroacetate-treated patients and 10.4 +/- 5.5 mmol per liter in the placebo group, and the mean initial arterial-blood pH values were 7.24 +/- 0.12 and 7.24 +/- 0.13, respectively. Eighty-six percent of the patients required mechanical ventilation, and 74 percent required pressor agents, inotropic drugs, or both because of hypotension. The arterial-blood lactate concentration decreased 20 percent or more in 83 (66 percent) of the 126 patients who received dichloroacetate and 45 (36 percent) of the 126 patients who received placebo (P = 0.001). The arterial-blood pH also increased more in the dichloroacetate-treated patients (P = 0.005). The absolute magnitude of the differences was small, however, and they were not associated with improvement in hemodynamics or survival. Only 12 percent of the dichloroacetate-treated patients and 17 percent of the placebo patients survived to be discharged from the hospital. Dichloroacetate treatment of patients with severe lactic acidosis results in statistically significant but clinically unimportant changes in arterial-blood lactate concentrations and pH and fails to alter either hemodynamics or survival.
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              Lactic acidosis in critical illness

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                Author and article information

                Journal
                AJN
                Am J Nephrol
                10.1159/issn.0250-8095
                American Journal of Nephrology
                S. Karger AG
                0250-8095
                1421-9670
                2005
                February 2005
                22 March 2005
                : 25
                : 1
                : 55-63
                Affiliations
                Fresenius Dialysis Centers, Chicago, Ill., USA
                Article
                84141 Am J Nephrol 2005;25:55–63
                10.1159/000084141
                15731550
                © 2005 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: 1, References: 62, Pages: 9
                Product
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/84141
                Categories
                In-Depth Topic Review

                Cardiovascular Medicine, Nephrology

                Acidosis, Intracellular pH, Ischemia, Glucose, Bicarbonate, Pyruvate, Lactate

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