title: Effects of TA-3090, a new calcium channel blocker, on myocardial substrate utilization in ischemic and nonischemic isolated working fatty acid-perfused rat hearts.
abstract: 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.
authors.affiliation: Department of Medicine, University of Alberta, Edmonton, Canada.
authors.forename: N J
authors.initials: NJ
authors.lastname: Davies
authors.forename: J J
authors.initials: JJ
authors.lastname: McVeigh
authors.forename: G D
authors.initials: GD
authors.lastname: Lopaschuk
mesh_terms: D000332:Aerobiosis; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D003326:Coronary Circulation; D003327:Coronary Disease / Q000378:metabolism*; D004110:Diltiazem / Q000031:analogs & derivatives* / Q000494:pharmacology; D005227:Fatty Acids / Q000494:pharmacology*; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis; D006321:Heart / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D010084:Oxidation-Reduction; D010168:Palmitates / Q000378:metabolism; D051381:Rats; D012016:Reference Values
chemical_list: D002121:Calcium Channel Blockers; D005227:Fatty Acids; D010168:Palmitates; C056595:clentiazem; D004110:Diltiazem; D005947:Glucose