ENERGY METABOLISM IN THE REVERSIBLE AND IRREVERSIBLE PHASES OF SEVERE MYOCARDIAL ISCHEMIA

High energy phosphate (HEP) utilization and depletion as well as the production and distribution of catabolic products of adenine nucleotides were studied in ischemic dog hearts in order to characterize the transition from reversible to irreversible cell injury. Severe ischemia, induced by coronary occlusion in vivo was compared to total ischemia, in vitro. Much of the creatine phosphate (CP) was lost within the first one to three minutes. During severe ischemia in vivo, adenosine triphosphate (ATP) was depleted to only 35% of control by 15 minutes (when myocytes are still reversibly injured) and to less than 10% by 40 minutes (at which time irreversible injury has occurred). HEP production from anaerobic glycolysis was estimated from the rate of accumulation of myocardial lactate. HEP production ceased when the ATP was less than 0.4 μmol/g wet weight (control = 5–6). Prior to this time, 80% of the HEP which had been utilized in ischemia had been derived from anaerobic glycolysis whereas 20% came from pre-existing stores of CP and ATP. ATP depletion was paralleled by dephosphorylation of adenine nucleotides. The lost nucleotides were recovered stoichiometrically as adenosine, inosine, hypoxanthine, and xanthine in both models of ischemia. When myocardium was reperfused after 15 minutes of ischemia, these nucleosides and bases were lost to the systemic circulation, and repletion of adenine nucleotides was incomplete for as long as four days, apparently because both de novo and salvage pathways of adenine nucleotide synthesis are slow in myocardium. Further studies were done to assess the nature of the associations between the decreasing ATP of the ischemic tissue and the onset of defects in high energy phosphate regeneration, cell volume and ion regulation, and/or membrane permeability. Slices of control tissue from tissue injured by various periods of total ischemia were incubated in oxygenated Krebs Ringer's phosphate medium containing 14 C-inulin. As long as the ATP of the tissue was not depleted below 5 μmoles/g dry weight prior to incubation, no cellular abnormalities were detected. However, lower ATP levels were associated with depressed high energy phosphate resynthesis and failure of cell volume regulation. Overt membrane damage, as measured by an increased inulin diffusible space, was detected after the tissue ATP content decreased to less than 2.0 μmoles/g dry weight. Thus, cellular viability (reversible injury) was retained despite a modest and persistent ATP depletion, but there was a close assocation between marked ATP depletion and the failure of the damaged tissue to regenerate high energy phosphates and to preserve cell volume and ionic regulation (irreversible injury).