Role of calcium in acute hyperthermic myocardial injury

Hyperthermic Myocardial Injury. Introduction: We hypothesized that intracellular calcium overload may play an important role in heat-induced myocardial injury. This postulate was investigated using a model of isolated guinea pig papillary muscle in which resting tension was measured as an indirect indicator of cytosolic free-calcium concentration and the fluorescence changes of Fluo-3 AM dye was measured as a direct indicator of cytosolic free-calcium concentration. Methods and Results: Excised guinea pig right ventricular papillary muscles were attached to a force transducer in a high-flow tissue bath and superfused 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 seconds and then returned to 37.0 degreesC, Hyperthermia caused a reversible increase 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 intracellular calcium content. Inhibition of the sarcoplasmic reticulum calcium pump with 20 muM thapsigargin resulted in irreversible contracture of the papillary muscles at temperatures between 45 degrees and 50 degreesC and significant increases in Fluo-3 fluorescence at 48 degreesC. Blockade of sarcolemmal calcium channels with 0.5 mM cadmium or 40 muM verapamil did not attenuate the heat-induced increase in resting tension and Fluo-3 fluorescence. Conclusion: Hyperthermia causes an increase in resting tension of cardiac muscle that most likely is mediated by a calcium channel-independent increase in calcium permeability of the sarcolemmal membrane and/or release of stored intracellular calcium.