Regulation of glycolysis in the ischemic and the anoxic myocardium

Experiments were done in dogs with various durations of myocardial anoxia in the following conditions: (1) so-called ischemic cardiac arrest in normo- or hypothermia; (2) anoxic perfusion of the heart with and without added glucose; (3) ischemia with cardioplegia in normo- or hypothermia. Even after a pronounced reduction of the myocardial energy demands following cardioplegia and/or hypothermia, anaerobic glycolytic energy production is insufficient to cover the myocardial energy demands during ischemia. When the oxygen tension becomes critical in the ischemic myocardium (pO2 < 5 mmHg) the high energy phosphates—at first mainly phosphocreatine—are broken down and lactate is produced. At this very early stage of ischemia the adenine nucleotides show only minor changes in their concentrations. The transition from aerobic to anaerobic energy production (Pasteur-effect) leads to a 20-fold increase in the glycolytic flux. The Pasteur-effect leads to an activation of phosphorylase, hexokinase, phosphofruktokinase and pyruvate kinase and probably to activity changes of glycerinealdehyde phosphate-dehydrogenase or phosphoglycerate kinase. Glycolytic flux is controlled by the above mentioned enzymes and in addition by aldolase- and phosphoglucomutase reaction depending on the experimental conditions and the duration of ischemia. Reduction of myocardial energy demands by cardioplegia and/or hypothermia leads to a corresponding reduction of lactate production. This is related to changes in the activity of the phosphofructokinase reaction. Independent of the experimental conditions anaerobic energy production in the ischemic myocardium can only cover 65 to 70% of total anaerobic energy demand. In a heart perfused with a solution free of oxygen and glucose, glycolysis is able to cover 75 to 80% of the anaerobic energy demand; by adding glucose to the perfusate this value can be increased to 85 to 90%. Only 1 to 10% of the glycolytic enzyme activities as measured in vitro can be utilized in vivo for lactate production under anaerobic conditions. An exception is the activity of hexokinase which in vivo can be about 20% of its maximal in vitro activity. Enzymes of tricarboxylic acid cycle and of the respiratory chain operate in vivo nearer their maximal activity determined in vitro (20 to 60%). The glycolytic flux in the ischemic myocardium is mainly limited by the phosphofructokinase reaction. Only during the earliest stages of ischemia does activation of phosphorylase determine lactate production. When the myocardial ATP content has fallen to about 3.5 μmol/g wet weight (i.e. almost half of normal) the phosphoglucomutase reaction becomes the rate-limiting step of glycolysis; the ATP values of 3.5 μmol/g correlate with the limit of tolerated myocardial ischemia under clinical conditions. The cessation of lactate production is due to lack of ATP for the phosphorylation of fructose-6-phosphate to fructose diphosphate. This happens at a myocardial ATP-content < 2 μmol/g wet weight and correlates with the theoretical limit of tolerated myocardial ischemia. In the anoxic perfused heart glycolytic flux is not limited by the phosphofructokinase reaction. Under these conditions no intracellular acidosis builds up and phosphofructokinase is not inactivated. Thus lactate production is more active than in the ischemic myocardium. As a consequence of the greater activity of phosphofructokinase glucose-6-phosphate does not accumulate, therefore—unlike under ischemic conditions—hexokinase is active and glucose utilized.