Effects of treatment with pyruvate and tromethamine in experimental myocardial ischemia.
Failure of glycolysis to increase sufficiently to supply optimal levels of energy production in ischemic heart muscle is due in part to the cummulative restrainst of acidosis on rate-limiting enzymes, particularly glyceraldehyde-3-phosphate dehydrogenase. In an effort to modify this inhibition and salvage jeopardized myocardium, treatment with excess levels of pyruvate and tromethamine (Tris), designed to buffer intracellular hydrogen ion accumulations and improve the oxidation-reduction ratio, NAD+/NADH, was tested in 59 swine hearts in two separate preparations of global and regional ischemia. Global ischemia, per se, caused hemodynamic deterioration and shortened survival time (44.3 +/- 3.1 minutes). Myocardial oxygen consumption, fatty acid oxidation, and glucose uptake were all significantly (P less than 0.001) reduced as were estimates of glycolysis and tissue stores of creatine phosphate and ATP (P less than 0.01). Although treatment with Tris alone was inconclusive, administrations of pyruvate (40-50 mM) buffered with Tris (added directly into the coronary perfusate) effected an improvement in mechanical function and a significant prolongation in survival time (56.9 +/- 2.6 minutes. P less than 0.01). Glycogenolysis was enhanced and levels of key glycolytic intermediates were reduced, suggesting an acceleration of glycolytic flux. Excess levels of pyruvate (1.52 +/- 0.48 mumol/ml of coronary perfusate) provided added substrate for oxidation and led to a greater than 5-fold incrase in rates of pyruvate decarboxylation as compared to untreated ischemic hearts...
D000818:Animals; D003327:Coronary Disease / Q000188:drug therapy* / Q000378:metabolism; D004195:Disease Models, Animal; D004734:Energy Metabolism / Q000187:drug effects; D005260:Female; D005947:Glucose / Q000378:metabolism; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D011773:Pyruvates / Q000494:pharmacology / Q000627:therapeutic use*; D013552:Swine; D014325:Tromethamine / Q000494:pharmacology / Q000627:therapeutic use*
D011773:Pyruvates; D014325:Tromethamine; D005947:Glucose