164 



HANDBOOK OF PHYSIOLOGY 



CIRCULATION I 



even after long incubations. Exposure to higher 

 concentrations of lithium o\er periods of several 

 hours caused irreversible damage to the muscle 

 (228). Many years later it was shown by Hodgkin c& 

 Katz (144) and by Huxley & Stampfli (154) that 

 not only resting potentials but also action potentials 

 of nerve fibers were unaltered when the bathing 

 medium sodium was replaced by lithium. However, 

 prolonged exposure to lithium solutions over periods 

 of many hours is associated with depolarization of 

 the cell membrane which in the experience of Gallego 

 & Lorente de No {82) begins about 2 hours following 

 expo.sure to lithium and is progressive thereafter. 

 The recent studies of Keynes & Swan (173) on frog 

 sartorius muscle show that the efflux of lithium ion 

 from the frog muscle is more than 10 times slower 

 than the efflux of sodium under similar conditions; 

 and though sodium efflux is diminished in potassium- 

 free solutions the inovemcnt of lithium is not affected 

 by external potassium. Furthermore, whereas sodium 

 can be transported out of the cell against an electro- 

 chemical gradient, a lithium loaded muscle cannot 

 eject lithium into an outside .solution in which all 

 the sodium is replaced by lithium. All this evidence, 

 taken together, strongly suggests that lithium efflux is 

 completely or for the most part passive, and that 

 active transport of lithium out of the cell is negligible 

 if it exists at all. 



Some active transport of lithium by frog skin (341) 

 has indeed been demonstrated, but certainly in the 

 case of the frog skin lithium transport is quite small 

 compared to that of sodium. Maizels (202) has 

 shown that in human red blood cells the inward 

 passive moxements of sodium and lithium have 

 roughlv equal rate constants, but there is little or no 

 active outward movement of lithium. 



From the studies cited above, one may emerge 

 with the following picture of lithium action. At least 

 in tiie case of striated muscle and ncr\e, it appears 

 that lithium shares with sodium low cellular mem- 

 brane permeability when the membrane is in the 

 resting state. In \iew of the fact that tlie action poten- 

 tial is thought to be due to an inward sodium current 

 which occurs as a result of a sudden change in mem- 

 brane permeability during depolarization, and in 

 view^ of the fact that the action potential in lithium 

 solutions is indistinguishable from that in sodium, it 

 appears that during acti\ity the membrane becomes 

 highly permeable not only to sodium but also to 

 lithium. In contrast to the passive membrane qualities, 

 it appears that tiic cellular capacity for transporting 

 lithium out of the cell against an electrical and 

 chemical potential gradient is very small compared 

 to that for sodium. Because of the low cell membrane 



permeability for lithium the replacement of external 

 sodium by lithium docs not result in any immediate 

 cellular depolarization, but a finite permeability to 

 lithium combined with a negligible cellular capacity 

 for pumping litiiium out of the cell results in a slow 

 accumulation of lithium, a decrease in intracellular 

 pota.ssium, and a progressive depolarization of the 

 cell membrane. 



The effect of replacing sodium by lithium on the 

 contractility of the heart is rather promptly seen, in 

 contrast to the results in skeletal muscle. Thus many 

 investigators (iio, 191, 223, 342) have found that in 

 lithium solutions the contractile force of isolated 

 heart is increased and may be followed shortly 

 thereafter by contracture. The difference between 

 heart and skeletal muscle in this respect is probably 

 related to the fact that in ion-free solutions heart 

 muscle loses rather readily a certain fraction of the 

 intracellular cation, and, as we have noted previously 

 (section 11), monovalent cation loss from cardiac 

 muscle is associated with increased tension and 

 finallv contracture. The lithium solution (if heart 

 muscle membrane has a low permeability to lithium 

 as do those of nerve and skeletal muscle) is therefore 

 in this respect like an isomotic nonelcctrolyte solution, 

 and both intracellular sodium and potassium will be 

 lost without a corresponding gain in cellular lithium. 

 The earlv effects of lithium on contractility of heart 

 muscle are probably related to this phenomenon. 

 Later, as more and more potassium is lost, the cellular 

 membrane potential will decrea.se to low levels as it 

 does in ner\e and skeletal muscle. [For references on 

 the effects of lithium on the electrocardiogram 

 which appear in papers on clinical lithium toxicity, 

 the reader is referred to the review by Schou (265).] 



Rubidium 



Just as lithiimi and sodium have certain proper- 

 ties in common, the remaining available members of 

 the alkali metal group, rubidium and cesium, arc to 

 some extent comparable to potassium in certain of 

 their properties. The gross chemical similarities 

 between the rubidium and potassium ion can be 

 appreciated at several le\els of complexity. For 

 example, enzymes activated by potassium can 

 frequently he activated by rubidium or ammonium 

 (265). In whole animal studies it has been noted 

 that the disappearance rates of a tracer dose of 

 rubidium injected simultaneously with radioactive 

 potassium into i^lood plasma are quite comparable 

 (37) and many investigators during the past half 

 century have found that solutions of rubidium chloride 

 can depolarize nerve or muscle memiiranes in a 



