PHYSICOCIIKMICAL FACTORS— BROWN 5 



activaliun. Or for that matter whether a reduction in activity with increasing tem- 

 perature depends on the increase in rate of some interfering reaction or a reversihle 

 thermal inactivation of a controlling enzyme. In the former a Type I inhihitor could 

 lead to an increase in activity while in the latter a Type II would increase the inhihi- 

 tion. Clearly the extent to which the physical chemistry of enzymes may be applied 

 to cellular processes is limited l)y our knowledge of cellular physiology. 



In hypothermia considered at the cellular level the impairment of any cellular 

 activity arises when the energy essential for function is impaired either for the pri- 

 mary cause of anoxia or the secondary cause of an insufficient electrolyte balance 

 across the cell membrane, both stemming from an inadequate composition of the 

 extracellular fluid. In the light of the body of evidence on cellular function now 

 available, it seems certain that the locus of action of the above agents is on the cell 

 membrane. By acting there they tend to limit its capacity (a) to maintain the elec- 

 trical potential, (b) to excite, (c) to induce activation, and (d) to determine the 

 duration of the active state. Since the cardiac contractility is of such importance 

 in hypothermia it is appropriate to consider its temperature dependence and the 

 extent to which it depends on excitation and the activation cycle. 



The significant fact concerning the effect of temperature on the isometric tension 

 developed by an isolated strip of heart muscle is that all vertebrates exhibit a tem- 

 perature optimum. Thus the frog, turtle and cat have optima at 0°, 10° and 22° C, 

 respectively, the tension diminishing at lower or higher temperatures. In an unfa- 

 tigued heart the tension developed at the optimum temperature is the maximum 

 which can be developed at any temperature and pressure or in the presence of drugs 

 such as jj strophanthin. If the rate of stimulation is increased above a certain limit, 

 the tension at temperatures below or at the optimum is reduced. But above the opti- 

 mum temperature, where treppe exists, the maximum tension may be attained pro- 

 vided a suitable rate of stimulation is employed at each temperature (Hajdu and 

 Szent Gyorgyi, 1952; Twente, 1955). 



Perhaps the most important fact with respect to tension and temperature is that 

 when the heart is treated with /3 strophanthin or if the Ca** is sufficiently increased, 

 the tension increases with temperature to the maximum level and maintains this 

 value at increasingly higher temperatures over the physiological range and treppe 

 is non-existent. In the turtle the maximum tension obtains from 9° to 34° C. When 

 the heart is in this state it requires a much higher rate of stimulation before the 

 tension is reduced. In the mammal the maximum tension is reached at about 22° C. 

 and it would be expected that increased Ca'\ digitalis, or /3 strophanthin would cause 

 this tension to be sustained up to 38° C, provided that the rate of beat were sub- 

 Dptimal. 



The view has been held by some that a heart in situ under normal physiological 

 conditions does not exhibit treppe. Although this may be so, it is certain that the 

 "treppe state" is readily induced by rather minor changes in the composition of the 

 extracellular fluid and it is quite probable that it would appear during progressive 

 hypothermic failure. If this were the case, it would be a very unfavorable situation 

 since the isometric tension becomes very dependent on heart rate. The fact that 

 digitalis, alkaloids, cortisone and other agents tend to stabilize the tension with 



