Role Of Calcium During Hyperthermia

This study was conducted with the goal of determining if hyperthermia increases the permeability of the plasma or mitochondrial membrane to Ca2+ and the effect of the resulting influx of Ca2+ upon cellular damage. Ca2+ can potentiate hyperthermic damage. Isolate rat hepatocytes are more sensitive to hyperthermia in high extra cellular Ca2+ and when treated with Ca2+ lonophore A23187. The degree of thermal sensitization is directly related to Ca2+ influx. In 15 mm Ca2+, Ca2+ influx due to increased permeability of the plasma membrane precedes loss of viability of hepatocytes. In 1-4 mm Cn2+, influx occurs during heating only after excessively long exposure to be the initial step in killing. Thus, Ca2+ influx at physiological concentrations of Ca2+ is not an early event in killing but it may plan important role in irreversibly programming a cell to death. Isolated mitochondria are very sensitive to elevated temperatures. Mitochondrial Ca2+ uptake is inhibited and mitochondrial Ca2+ release occurs in a dose dependent manner (81 and 100% release of accumulated Ca2+ occurs in 2 and 3 minutes respectively at 43 c) while no Ca2+ release is observed during the same time at lower temperatures. Differential scanning calorimetry (DSC) profiles indicate thermal denaturation of mitochondrial protein above 40 c, which may then cause the observed release of Ca2+. This suggests that release of Ca2+ by mitochondria may be more sensitive to hyperthermia than leakage across the plasma membrane. From the clinical point of view, increased calcium may theoretically offer an alternative approach to the design of hyperthermic protocols if a way can be found to differentially increase, even slightly, the Ca2+ permeability of cells in a tumor.