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 microU/ml insulin. Glycolysis and glucose oxidation rates were determined in aerobic and reperfused ischemic hearts perfused with [3H]/[14C]glucose, whereas fatty acid oxidation rates were determined under similar conditions in hearts perfused with [14C]palmitate. Addition of diltiazem (0.8 microM) 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 mumol/min.g dry wt. in control and diltiazem-treated hearts, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)
Lopaschuk
G D
GD
Department of Pediatrics, University of Alberta, Edmonton, Canada.
Barr
R
R
Wambolt
R
R
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism; D003327:Coronary Disease / Q000378:metabolism*; D004110:Diltiazem / Q000494:pharmacology*; D004734:Energy Metabolism / Q000187:drug effects; D006019:Glycolysis / Q000187:drug effects*; D066298:In Vitro Techniques; D015425:Myocardial Reperfusion; D009206:Myocardium / Q000378:metabolism*; D010084:Oxidation-Reduction; D011817:Rabbits
D000255:Adenosine Triphosphate; D004110:Diltiazem; D002118:Calcium