title: Pyruvate-enhanced phosphorylation potential and inotropism in normoxic and postischemic isolated working heart. Near-complete prevention of reperfusion contractile failure.
abstract: Bioenergetic and hemodynamic consequences of cellular redox manipulations by 0.2-20 mM pyruvate were compared with those due to adrenergic stress (0.7-1.1 microM norepinephrine) using isolated working guinea-pig hearts under the conditions of normoxia, low-flow ischemia, and reperfusion. 5 mM glucose (+ 5 U/l insulin) + 5 mM lactate were the basal energy-yielding substrates. To stabilize left ventricular enddiastolic pressure, ventricular filling pressure was held at 12 cmH2O under all conditions; this preload control minimized Frank-Starling effects on ventricular inotropism. Global low-flow ischemia was induced by reducing aortic pressure to levels (20-10 cmH2O) below the coronary autoregulatory reserve. Reactants of the creatine kinase, including H+ and other key metabolites, were measured by enzymatic, HPLC, and polarographic techniques. In normoxic hearts, norepinephrine stimulations of inotropism, heart rate x pressure product, and oxygen consumption (MVO2) were associated with a fall in the cytosolic phosphorylation potential [( ATP]/[( ADP].[Pi]] as judged by the creatine kinase equilibrium. In contrast, infusion of excess pyruvate (5 mM) markedly increased [ATP]/[( ADP].[Pi]) and ventricular work output, while intracellular phosphate decreased; MVO2 remained constant under the same conditions. During reperfusion following ischemia, pyruvate effected striking and concentration-dependent increases in MVO2, phosphorylation potential, and inotropism. Pyruvate dehydrogenase flux was augmented during reperfusion hyperemia followed by near-complete recoveries of [ATP]/([ADP].[Pi]), contractile force, heart rate x pressure product, and MVO2 in the presence of 5-10 mM pyruvate. Pyruvate also attenuated ischemic adenylate degradation. Omission of glucose from the perfusion medium rendered pyruvate ineffective in postischemic hearts. Similarly, excess lactate (5-15 mM) or acetate (5 mM) failed to reenergize reperfused hearts and severe depressions of MVO2 and inotropism developed despite the presence of glucose. Apparently, subcellular redox manipulations by pyruvate dissociated stimulated mitochondrial respiration and increased inotropism from low cytosolic phosphorylation potentials. This was evidence against the extramitochondrial [ADP].[Pi]/[ATP] ratio being the primary factor in the control of mitochondrial respiration. The mechanism of pyruvate enhancement of inotropism during normoxia and reperfusion is probably multifactorial. Thermodynamic effects on subcellular [NADH]/[NAD+] ratios are coupled with a rise in the cytosolic [ATP]/[( ADP].[Pi]) ratio at constant (normoxia) or increased (reperfusion) MVO2.(ABSTRACT TRUNCATED AT 400 WORDS)
authors.affiliation: Department of Physiology, F. E. Hebert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD 20814-4799.
authors.forename: R
authors.initials: R
authors.lastname: Bünger
authors.forename: R T
authors.initials: RT
authors.lastname: Mallet
authors.forename: D A
authors.initials: DA
authors.lastname: Hartman
mesh_terms: D000085:Acetates / Q000494:pharmacology; D000818:Animals; D003326:Coronary Circulation / Q000187:drug effects; D003327:Coronary Disease / Q000378:metabolism* / Q000517:prevention & control; D003331:Coronary Vessels / Q000378:metabolism; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D004734:Energy Metabolism / Q000187:drug effects; D005947:Glucose / Q000494:pharmacology; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D007773:Lactates / Q000494:pharmacology; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D009638:Norepinephrine / Q000494:pharmacology; D010084:Oxidation-Reduction / Q000187:drug effects; D010477:Perfusion; D010766:Phosphorylation; D011773:Pyruvates / Q000494:pharmacology*; D019289:Pyruvic Acid
chemical_list: D000085:Acetates; D007773:Lactates; D011773:Pyruvates; D019289:Pyruvic Acid; D005947:Glucose; D009638:Norepinephrine