title: Functional response of the isolated, perfused normoxic heart to pyruvate dehydrogenase activation by dichloroacetate and pyruvate.
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.
authors.affiliation: Department of Biomedical Engineering, The George Washington University, GWU Science and Engineering Hall, 800 22nd Street NW, Suite 5000, Washington, DC, 20052, USA.
authors.forename: Rafael
authors.initials: R
authors.lastname: Jaimes
authors.affiliation: Department of Biomedical Engineering, The George Washington University, GWU Science and Engineering Hall, 800 22nd Street NW, Suite 5000, Washington, DC, 20052, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Kuzmiak-Glancy
authors.affiliation: Department of Biomedical Engineering, The George Washington University, GWU Science and Engineering Hall, 800 22nd Street NW, Suite 5000, Washington, DC, 20052, USA.
authors.forename: Daina M
authors.initials: DM
authors.lastname: Brooks
authors.affiliation: Department of Pharmacology and Physiology, The George Washington University, Washington, DC, 20052, USA.
authors.forename: Luther M
authors.initials: LM
authors.lastname: Swift
authors.affiliation: Department of Pharmacology and Physiology, The George Washington University, Washington, DC, 20052, USA.
authors.forename: Nikki G
authors.initials: NG
authors.lastname: Posnack
authors.affiliation: Department of Biomedical Engineering, The George Washington University, GWU Science and Engineering Hall, 800 22nd Street NW, Suite 5000, Washington, DC, 20052, USA. phymwk@gwu.edu.|Department of Pharmacology and Physiology, The George Washington University, Washington, DC, 20052, USA. phymwk@gwu.edu.
authors.forename: Matthew W
authors.initials: MW
authors.lastname: Kay
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D003999:Dichloroacetic Acid / Q000494:pharmacology*; D005947:Glucose / Q000378:metabolism; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D000067268:Isolated Heart Preparation; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism*; D009243:NAD / Q000378:metabolism; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism*; D019289:Pyruvic Acid / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016276:Ventricular Function
chemical_list: D011768:Pyruvate Dehydrogenase Complex; D009243:NAD; D019289:Pyruvic Acid; D003999:Dichloroacetic Acid; D005947:Glucose; D002118:Calcium
keywords: Cardiac; Dichloroacetate; NADH; Pyruvate dehydrogenase