NDLI: Functional response of the isolated, perfused normoxic heart to pyruvate dehydrogenase activation by dichloroacetate and pyruvate

Content Provider	Springer Nature Link
Author	Jaimes, Rafael Kuzmiak Glancy, Sarah Brooks, Daina M. Swift, Luther M. Posnack, Nikki G. Kay, Matthew W.
Copyright Year	2015
Abstract	Dichloroacetate (DCA) and pyruvate activate pyruvate dehydrogenase (PDH), a key enzyme that modulates glucose oxidation and mitochondrial NADH production. Both compounds improve recovery after ischemia in isolated hearts. However, the action of DCA and pyruvate in normoxic myocardium is incompletely understood. We measured the effect of DCA and pyruvate on contraction, mitochondrial redox state, and intracellular calcium cycling in isolated rat hearts during normoxic perfusion. Normalized epicardial NADH fluorescence (nNADH) and left ventricular developed pressure (LVDP) were measured before and after administering DCA (5 mM) or pyruvate (5 mM). Optical mapping of Rhod-2AM was used to measure cytosolic calcium kinetics. DCA maximally activated PDH, increasing the ratio of active to total PDH from 0.48 ± 0.03 to 1.03 ± 0.03. Pyruvate sub-maximally activated PDH to a ratio of 0.75 ± 0.02. DCA and pyruvate increased LVDP. When glucose was the only exogenous fuel, pyruvate increased nNADH by 21.4 ± 2.9 % while DCA reduced nNADH by 21.4 ± 6.1 % and elevated the incidence of premature ventricular contractions (PVCs). When lactate, pyruvate, and glucose were provided together as exogenous fuels, nNADH increased with DCA, indicating that PDH activation with glucose as the only exogenous fuel depletes PDH substrate. Calcium transient time-to-peak was shortened by DCA and pyruvate and SR calcium re-uptake was 30 % longer. DCA and pyruvate increased SR calcium load in myocyte monolayers. Overall, during normoxia when glucose is the only exogenous fuel, DCA elevates SR calcium, increases LVDP and contractility, and diminishes mitochondrial NADH. Administering DCA with plasma levels of lactate and pyruvate mitigates the drop in mitochondrial NADH and prevents PVCs.
Starting Page	131
Ending Page	142
Page Count	12
File Format	PDF
ISSN	00316768
Journal	Pflügers Archiv
Volume Number	468
Issue Number	1
e-ISSN	14322013
Language	English
Publisher	Springer Berlin Heidelberg
Publisher Date	2015-07-05
Publisher Place	Berlin, Heidelberg
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	Pyruvate dehydrogenase Dichloroacetate NADH Cardiac Human Physiology
Content Type	Text
Resource Type	Article
Subject	Physiology Physiology (medical) Clinical Biochemistry

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