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• W2162801391 endingPage "H1006" @default.
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• W2162801391 abstract "The mechanism by which inhibition of Na+/H+ exchanger (NHE) reduces cell death in ischemic-reperfused myocardium remains controversial. This study investigated whether cariporide could inhibit mitochondrial NHE during ischemia, delaying H+ gradient dissipation and ATP exhaustion. Mouse cardiac myocytes (HL-1) were submitted to 1 h of simulated ischemia (SI) with NaCN/deoxyglucose (pH 6.4), with or without 7 microM cariporide, and mitochondrial concentration of Ca2+ (Rhod-2), 2', 7'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein (BCECF) and the charge difference across the mitochondrial membrane potential (Deltapsim, JC-1) were assessed. ATP content was measured by bioluminescence and mitochondrial swelling by spectrophotometry in isolated mitochondria. Cariporide significantly attenuated the acidification of the mitochondrial matrix induced by SI without modifying Deltapsim decay, and this effect was associated to a delayed ATP exhaustion and increased mitochondrial Ca2+ load. These effects were reproduced in sarcolemma-permeabilized cells exposed to SI. In these cells, cariporide markedly attenuated the fall in mitochondrial pH induced by removal of Na+ from the medium. In isolated mitochondria, cariporide significantly reduced the rate and magnitude of passive matrix swelling induced by Na+ acetate. In isolated rat hearts submitted to 40-min ischemia at different temperatures (35.5 degrees, 37 degrees, or 38.5 degrees C) pretreatment with cariporide limited ATP depletion during the first 10 min of ischemia and cell death (lactate dehydrogenase release) during reperfusion. These effects were mimicked when a similar ATP preservation was achieved by hypothermia and were abolished when the sparing effect of cariporide on ATP was suppressed by hyperthermia. We conclude that cariporide acts at the mitochondrial level, delaying mitochondrial matrix acidification and delaying ATP exhaustion during ischemia. These effects can contribute to reduce cell death secondary to ischemia-reperfusion." @default.
• W2162801391 created "2016-06-24" @default.
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• W2162801391 date "2003-09-01" @default.
• W2162801391 modified "2023-10-17" @default.
• W2162801391 title "Cariporide preserves mitochondrial proton gradient and delays ATP depletion in cardiomyocytes during ischemic conditions" @default.
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• W2162801391 doi "https://doi.org/10.1152/ajpheart.00035.2003" @default.
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