Experimental studies have shown that
calcium channel blockade has a protective effect on the ischemic myocardium. Although these agents may act by decreasing intracellular Ca2+ accumulation during reperfusion or to reduce
oxygen requirements by decreasing myocardial work load, recent evidence suggests that
calcium blockers may also favorably alter energy substrate metabolism in ischemic and reperfused myocardium. In this study,
TA-3090, a new
calcium channel blocker with minimal effect on myocardial work load, was used to study the effect of
calcium channel blockade on both myocardial substrate utilization and reperfusion recovery of ischemic hearts. Isolated working rat hearts were perfused at an 11.5 mm Hg preload and an 80 mm Hg afterload with
Krebs-Henseleit buffer containing 11 mM
glucose, 1.2 mM
palmitate, and 500 microunits/ml
insulin. In aerobically perfused spontaneously beating hearts, a 0.5 microM dose of
TA-3090 had a mild depressant effect on heart rate but no effect on peak systolic pressure development. In paced hearts (250 beats/min), 0.5 microM
TA-3090 had no effect on either peak systolic pressure development or contractility.
Fatty acid and
glucose oxidation was determined by measuring 14CO2 production in hearts perfused with either [14C]
palmitate or [14C]
glucose, respectively, whereas glycolysis was determined by measuring 3H2O production from [3H]
glucose. Under aerobic conditions,
fatty acid oxidation was not altered by
TA-3090, but a significant decrease in
glucose oxidation and glycolytic rates was observed. If hearts were subjected to a 30-minute period of no-flow
ischemia, the addition of 0.5 microM
TA-3090 to the perfusate before
ischemia significantly improved reperfusion recovery of mechanical function. The protective effects of
TA-3090 were not observed if
TA-3090 was added at the time of reperfusion and were not related to a depression of function before
ischemia.
TA-3090, added before
ischemia, significantly reduced
glycogen and
ATP depletion during no-flow
ischemia and also significantly decreased glycolytic rates in hearts subjected to low-flow
ischemia (coronary flow = 0.5 ml/min). Combined, our data suggest that the beneficial effects of
calcium channel blockade on the ischemic myocardium are not related solely to a decrease in myocardial work load or metabolic demand before
ischemia, but rather may in part be related to a decrease in myocardial energy demand during
ischemia itself, resulting in preservation of
ATP and a decrease in glycolysis. The decrease in glycolytic rates during
ischemia may also result in a reduction of glycolytic product accumulation during
ischemia.