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Interaction of Sodium Bicarbonate and Na+/H+ Exchanger Inhibition in the Treatment of Acute Metabolic Acidosis in Pigs

Lin, Xinchun MD1; More, Amar S. PhD2; Kraut, Jeffrey A. MD3; Wu, Dongmei PhD1,2

doi: 10.1097/CCM.0000000000000962
Online Laboratory Investigations

Objective: Administration of NaHCO3 does not improve cellular function or reduce the mortality of acute lactic acidosis. This might be related to aggravation of intracellular acidosis, but it could also be due to activation of Na+/H+ exchanger with a deleterious increment in intracellular calcium ([Ca2+]i). This study examined the impact of coadministration of NaHCO3 and a selective inhibitor of Na+/H+ exchanger, sabiporide on cardiovascular function, changes in proinflammatory cytokines, and organ function in a model of acute lactic acidosis produced by hemorrhagic hypotension followed by infusion of lactic acid.

Design: Experimental, prospective study.

Setting: Medical Center research laboratory.

Subjects: Male Yorkshire pigs.

Interventions: Anesthetized pigs were subjected to hypovolemia for 30 minutes and followed by DL-lactic acid infusion, and then either saline or sodium bicarbonate was infused.

Measurements and Main Results: Hypovolemia followed by a DL-lactic acid infusion resulted in severe acidemia with a blood pH ~6.8. Administration of NaHCO3 did not improve cardiovascular performance or decrease the levels of proinflammatory responses, whereas administration of sabiporide prior to acid or NaHCO3 infusion improved cardiopulmonary performance and blood oxygenation, reduced nuclear factor-κB activation, neutrophil accumulation, and proinflammatory cytokine production, and attenuated organ injury. Exposure of rat cardiac myocytes to a pH of 7.2 led to a marked increase of [Ca2+]i, and release of lactate dehydrogenase from cells which were further augmented after increase in external pH by addition of NaHCO3. Both the increase in [Ca2+]i and release of lactate dehydrogenase were attenuated in the presence of sabiporide.

Conclusions: Coadministration of Na+/H+ exchanger inhibitor with sodium bicarbonate improves cardiovascular performances, reduces proinflammatory responses, and attenuates organ injury. This improvement in these variables appears to be related to prevention of a rise in intracellular calcium occurring after both exposures to acid and bicarbonate.

1Department of Research, Mount Sinai Medical Center, Miami Beach, FL.

2Department of BIN Fusion Technology, Chonbuk National University, Jeonju, Korea.

3Division of Nephrology VHAGLA Healthcare System, UCLA David Geffen School of Medicine, Los Angeles, CA.

Supported, in part, by the Brain Korea 21 PLUS Project, National Research Foundation of Korea (NRF) and by the Basic Science Research Program through the NRF funded by the Ministry of Education, Science and Technology (2012007331), Korea.

Dr. Kraut received support for article research from University of California Los Angeles Academic Senate and the Veterans Administration. Dr. Wu received support from the U.S. Army Medical Research and Material Command (grant W81XWH-06-1-0719) and received support for article research from the Department of Defense and National Research Foundation of Korea. The remaining authors have disclosed that they do not have any potential conflicts of interest.

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