Analysis of control of glycolysis in ischemic hearts having heterogeneous zones of anoxia

Abstract

The effects of hypercapnia have been studied in rat hearts perfused with glucose and insulin. At pH 6.7 to 6.8, two different responses were observed. One was characterized by a rapid decrease in pressure development followed by a gradual recovery of contractile function. The tissue was uniformly aerobic, ATP levels were well maintained, the cytosolic and mitochondrial pyridine nucleotides were significantly more oxidized than during control conditions, and glycolytic flux was decreased due to inhibition of phosphofructokinase. In the second type of response, there was an uneven distribution of coronary perfusion with anoxic areas appearing in regions where flow was most restricted, and myocardial function remained severely impaired. Unperfused vessels and anoxic tissue were shown to exist throughout the myocardium under these conditions. Whole-tissue ATP levels were significantly decreased and NADH levels increased, reflecting impaired electron transport and oxidative phosphorylation. The problem of interpretation of total tissue metabolite contents in heterogeneously oxygenated tissue was resolved by calculation of the proportion of aerobic to anaerobic tissue in these hearts. In the anaerobic portions of ischemic hearts, glycolysis was inhibited at the level of glyceraldehyde 3-P dehydrogenase due to increased cytosolic NADH and decreased intracellular pH. Calculations of cytosolic and mitochondrial ATP/ADP ratios and phosphate potentials suggest (a) that the cytosolic free Mg2+ concentration was 0.6 to 0.7 m M in aerobic hearts, but was much lowerin anaerobic hearts, (b) that the rate of respiration did not depend solely on the cytosolic phosphate potential but was also influenced by the mitochondrial NAD redox state, and (c) that the estimated phosphorylation potential of aerobic hearts was 3.5 kcal/mol higher in the cytosol than in the mitochondria.