EFFECTS OF DILTIAZEM ON GLYCOLYSIS AND OXIDATIVE-METABOLISM IN THE ISCHEMIC AND ISCHEMIC REPERFUSED HEART

We have recently demonstrated that calcium channel blockers can protect the ischemic myocardium at concentrations which do not decrease myocardial workload or metabolic demand before ischemia. In this study, we extended these observations by determining what effect the calcium channel blocker, diltiazem, has on overall myocardial energy substrate metabolism in aerobic, ischemic and reperfused ischemic hearts. Isolated working rat hearts were perfused at a 11.5-mm Hg preload, 80-mm Hg afterload, with Krebs-Henseleit buffer containing 11 mM glucose, 1.2 mM palmitate and 500-mu-U/ml insulin. Glycolysis and glucose oxidation rates were determined in aerobic and reperfused ischemic hearts perfused with [H-3]/[C-14]glucose, whereas fatty acid oxidation rates were determined under similar conditions in hearts perfused with [C-14]palmitate. Addition of diltiazem (0.8-mu-M) before subjecting hearts to a 30-min period of global no-flow ischemia resulted in a significant improvement in recovery of mechanical function (heart rate x developed pressure during reperfusion recovered to 28 and 53% of preischemic levels, in control and diltiazem-treated hearts, respectively). If diltiazem was added at reperfusion, no improvement of functional recovery was seen. Addition of diltiazem before or after ischemia had no effect on palmitate or glucose oxidation during reperfusion, but did significantly decrease rates of glycolysis during reperfusion. In hearts subjected to low-flow ischemia (coronary flow = 0.5 ml/min), diltiazem significantly decreased glycolytic rates during ischemia (glycolytic rates were 2.09 +/- 0.25 and 1.58 +/- 0.28-mu-mol/min.g dry wt. in control and diltiazem-treated hearts, respectively). These data suggest that the beneficial effects of diltiazem on reperfusion recovery of ischemic hearts is not due to an improvement of energy substrate utilization during reperfusion. Rather, it suggests that a decrease in energy demand and glycolysis during ischemia may be responsible for this beneficial effect. The decrease in glycolysis in diltiazem-treated hearts during the ischemia may also result in a decrease in the potential for glycolytic product accumulation during ischemia.