194 



THE CELL AND PROTOPLASM 



theory of stimulation depends on the num- 

 ber of phenomena it can explain. Above 

 all else, a satisfactory theory of stimulation 

 should offer an interpretation of the broad 

 facts of anesthesia, and every major theory 

 of stimulation has attempted to do this. In 

 living cells generallj', the effects of stimu- 

 lation are reversibly inhibited by two sorts 

 of anesthetics. One is the magnesium ion, 

 the other includes a variety of fat solvents 

 and fat soluble substances. Both types of 

 anesthetics are well-nigh universal. 



For all the older theories of stimulation 

 and anesthesia, the magnesium ion has 

 jiroved a stumbling block — so much so that 

 one of the leaders in the field of cellular 

 physiology has attempted to redefine anes- 

 thetics in order to exclude magnesium. 

 This in spite of the fact that there is no 

 more general anesthetic, inasmuch as mag- 

 nesium is effective on animals and tissues 

 from ameba to man. The difficulty in in- 

 terj^reting the effect of magnesium lies in 

 the fact that in every case that has been 

 studied magnesium anesthesia is specifi- 

 cally antagonized by calcium. Thus these 

 two bivalent and similar cations are op- 

 posed in their effects on the irritability of 

 living systems. 



In order to explain the action of mag- 

 nesium, it is not necessary to suppose that 

 its effect on protoplasm is the exact op- 

 posite of the effect of calcium. I have 

 suggested (1934) that magnesium behaves 

 like calcium but in far weaker fashion. 

 Thus, if the calcium of a cell is largely 

 replaced by magnesium, this would result 

 in the replacement of a very powerful ion 

 by one that acts in the same way but not 

 so strongly. In magnesium anesthesia it 

 may well be assumed that the calcium of 

 the cell cortex is to a considerable extent 

 replaced by magnesium. Upon stimulation 

 of such a magnesium treated cell, it is 

 magnesium rather than calcium that is re- 

 leased to the cell interior. If, as has been 

 indicated, some clotting reaction essen- 

 tially similar to the surface ])recipitation 

 reaction is involved in excitation, then it is 

 easy to understand why excitation should 

 be lacking when magnesium rather tlian 



calcium is thrown into the cell interior. 

 For it will be remembered that experiments 

 have shown that magnesium is over 100 

 times weaker than calcium in producing a 

 surface precipitation reaction. Here, then, 

 is an explanation of magnesium anesthesia 

 which seems to fit in with known facts. 

 No other theorj^ of stimulation has ever 

 offered any explanation whatsoever. 



Now let us consider anesthesia due to fat 

 solvents. Returning again to our theory 

 of protoplasmic stimulation, it will be re- 

 membered that it postulates two stages, 

 first a release of calcium from the cell 

 cortex, and second a clotting in the interior 

 of the cell as a result of the presence of 

 free calcium there. It can readily be 

 shown that fat solvents, such as ether, 

 higher alcohols, etc., do not prevent the 

 first stage of stimulation. Indeed, instead 

 of preventing the release of calcium from 

 the cortex of the cell, fat solvents actually 

 favor such a release. This is indicated by 

 the fact that solutions of fat solvents tend 

 to liquefy the cortex of the ameba cell. 

 Moreover, in the case of the Elodea leaf 

 cell with its oxalate indicator for calcium 

 within the vacuole, it can readily be shown 

 that fat solvents initiate rather than pre- 

 vent release of calcium from its bound state 

 within the protoplasm (Mazia and Clark 

 1936). 



Clearly, if our theory is to explain ether 

 anesthesia, we must postulate that dilute 

 solutions of ether (and other fat solvents) 

 are able to prevent the clotting reaction. 

 This is easy to show for cells as a whole, 

 and many years ago I was able to demon- 

 strate that dilute ether solutions prevent 

 the gelation which normality follows stimu- 

 lation in the sea-urchin eggs. But one 

 should be able to show also that ether and 

 other fat solvents suppress the surface 

 precipitation reaction, for this is regarded 

 as fundamentally akin to the clotting re- 

 action within the cell. My first attempts 

 in this direction were unsuccessful. Anes- 

 thetic concentrations of ether in sea water 

 do not in any sense suppress the surface 

 precipitation reaction as it occurs in the 

 sea-urcliin egg. This, for years, was a 



