Role of calcium in acute hyperthermic myocardial injury

Hyperthermic Myocardial Injury. Introduction: We hypothesized that intracel lular calcium overload may play an important role in heat-induced myocardia l injury. This postulate was investigated using a model of isolated guinea pig papillary muscle in which resting tension was measured as an indirect i ndicator of cytosolic free-calcium concentration and the fluorescence chang es of Fluo-3 AM dye was measured as a direct indicator of cytosolic free-ca lcium concentration. Methods and Results: Excised guinea pig right ventricular papillary muscles were attached to a force transducer in a high-flow tissue bath and superfu sed with Tyrode's solution at 37 degrees +/- 0.5 degreesC. The temperature was rapidly changed to between 38.0 degrees and 56.0 degreesC for 60 second s and then returned to 37.0 degreesC, Hyperthermia caused a reversible incr ease in resting tension at temperatures between 45 degrees and 50 degreesC and irreversible contracture at greater than or equal to 50 degreesC. Rapid cooling contracture experiments and experiments measuring fluorescence of myocytes loaded with 5 muM Fluo-3 AM dye demonstrated that the hyperthermia -induced rise in resting tension was likely due to an increase in intracell ular calcium content. Inhibition of the sarcoplasmic reticulum calcium pump with 20 muM thapsigargin resulted in irreversible contracture of the papil lary muscles at temperatures between 45 degrees and 50 degreesC and signifi cant increases in Fluo-3 fluorescence at 48 degreesC. Blockade of sarcolemm al calcium channels with 0.5 mM cadmium or 40 muM verapamil did not attenua te the heat-induced increase in resting tension and Fluo-3 fluorescence. Conclusion: Hyperthermia causes an increase in resting tension of cardiac m uscle that most likely is mediated by a calcium channel-independent increas e in calcium permeability of the sarcolemmal membrane and/or release of sto red intracellular calcium.