Role of calcium in acute hyperthermic myocardial injury.
BACKGROUND
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.


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 degrees C. The temperature was rapidly changed to between 38.0 degrees and 56.0 degrees C for 60 seconds and then returned to 37.0 degrees C. Hyperthermia caused a reversible increase in resting tension at temperatures between 45 degrees and 50 degrees C and irreversible contracture at > or =50 degrees C. Rapid cooling contracture experiments and experiments measuring fluorescence of myocytes loaded with 5 microM 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 microM thapsigargin resulted in irreversible contracture of the papillary muscles at temperatures between 45 degrees and 50 degrees C and significant increases in Fluo-3 fluorescence at 48 degrees C. Blockade of sarcolemmal calcium channels with 0.5 mM cadmium or 40 microM verapamil did not attenuate the heat-induced increase in resting tension and Fluo-3 fluorescence.


CONCLUSIONS
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.
Everett
T H
TH
Department of Internal Medicine, University of Virginia Health System, Charlottesville 22908, USA.
Nath
S
S
Lynch
C
C
Beach
J M
JM
Whayne
J G
JG
Haines
D E
DE
D000208:Acute Disease; D000818:Animals; D002118:Calcium / Q000502:physiology*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006168:Guinea Pigs; D006979:Hyperthermia, Induced; D008297:Male; D008955:Models, Cardiovascular; D009200:Myocardial Contraction / Q000187:drug effects; D015428:Myocardial Reperfusion Injury / Q000503:physiopathology*; D010210:Papillary Muscles / Q000187:drug effects / Q000293:injuries; D019284:Thapsigargin / Q000494:pharmacology
D002121:Calcium Channel Blockers; D004791:Enzyme Inhibitors; D019284:Thapsigargin; D002118:Calcium