Intermittent Ischemia: Energy Metabolism, Cellular Volume Regulation, Adenosine and Insights into Preconditioning

Abstract

Interruption of ischemia by brief reperfusions (I/R) is better tolerated by the heart than continuous ischemia. The present study aims to determine the metabolic profiles of isolated rat hearts during intermittent ischemia, the possible cardioprotective role of adenosine and the influence of I/R on intracellular volumes, using multinuclear NMR spectroscopy. After five I/R (5/5 min) episodes, hearts paced at 5 Hz developed pressures comparable to those of hearts continuously perfused for 50 min at 37°C (CP). Following the first 5 min episode of no-flow ischemia, [ADP] dropped from 72±9 to 43±5μm(P<0.001) and remained stable at the end of the following reperfusions, despite a 2.5–4-fold increase during each episode of 5 min ischemia. Intracellular volumes were stable during CP at a value of 2.50±0.06 ml/g dry weight, and decreased by 4, 8, and 12% after 1, 3, and 5 I/R episodes. The phosphorylation potentials decreased from 54±8 to 4 mm−1during each period of 5 min ischemia and were 40±6 and 28±6 mm−1after CP and I/R5, respectively. Cardiac glycogen had decreased during 50 min of CP from 103±13 to 81±9μmol/g dry weight and lactate production was 116±15μmol/heart. Five I/R episodes decreased glycogen to 46±7μmol/g dry weight (P<0.005vCP) and increased lactate efflux to 262±31μmol/heart (P<0.005vCP). These findings suggest that a brief ischemia/reperfusion episode increases anaerobic metabolism of exogenous glucose, reduces [ADP] and induces cellular shrinkage. Administration of the adenosine receptor blocker 8-phenyl theophylline (8PT) during intermittent perfusion depressed the developed pressure to 78±7%, accentuated the decrease in phosphorylation potential (14±4 mm−1), abolished cellular shrinkage, reduced lactate efflux and blunted the decrease in ADP following the first I/R episode. In variance, no detectable changes were observed during intermittent ischemia when the ATP-sensitive potassium channel blocker glibenclamide was administered. These data demonstrate: (a) a brief episode of ischemia/reperfusion stimulates anaerobic metabolism of exogenous glucose and lowers intracellular ADP concentration; (b) adenosine receptors are partially responsible for the glycolytic stimulation during intermittent ischemia; (c) cellular shrinkage is related to the rate of glycolysis during intermittent ischemia/reperfusion.