244 



HANDBOOK OF PHYSIOLOGY 



CIRCULATION I 



involve the same unknown function of distance; 

 therefore their ratio is simply 





[S]„ 



.FZgE/RT ^ FZgCS-Ea'/^T 



(5) 



All the terms in this equation can be measured 

 experimentally. If the values obtained in a particular 

 experiment do not satisfy equation 5, it is presumed 

 that the ion in question is actively transported. This 

 test is similar to the use of Nernst's equation to see if 

 an ion is in electrochemical equilibrium. The flux 

 ratio test is superior, however, because it will dis- 

 tinguish between an ion distributed at disequilibrium 

 but in a steady state due to active transport and one 

 that is in disequilibrium because of a nonsteady state 

 where the concentrations are changing. 



ENERGETICS. The conclusion that an ion not meeting 

 the flux ratio criterion is actively transported is 

 stringently limited by the fact that the power required 

 for the transport must be less than the total power 

 production of the cell. The transport of Na+ in frog 

 skeletal muscle meets this condition (46, 84). If the 

 efflux of Na+ in these cells is considered to be one half 

 active and one half exchange diffusion (the passive 

 efflux is negligible) 10 to 20 per cent of the resting 

 metabolism is required to maintain the Na+ efflux, 

 provided the efficiency is 50 per cent. The minimum 

 power recjuired is simply the product of the active 

 efflux and Amnb- 



THE NA+-K+ EXCHANGE PUMP. Rcsults of experiments 

 on a number of tissues support the view that the 

 active extrusion of Na"*" and the uptake of K+ are at 

 least loosely linked, the ejection of one Na"*" usually 

 being accompanied by the uptake of one K+. This 

 process is frequently referred to as the Na+-K+ ex- 

 change pump, the Na+-K+ pump or simply the Na+ 

 pump. Hodgkin & Keynes' (53, 64) findings on 

 Na+-K+ exchange in giant axons of Sepia form a com- 

 pact summary of the direct experimental evidence 

 that part of Na+ efflux and of K+ influx are active 

 and coupled. These data confirm the theoretical 

 reasons given above for supposing that there are 

 active components of the Na+ and K+ fluxes, a) Na+ 

 efflux is a direct function of [Na+]i; Keynes & Swan 

 (85) have recently found that at low [Na+]i's, efflux 

 is proportional to the third power of [Na+Ji in frog 

 skeletal muscle, h) In Sepia Na+ efflux is abolished by 

 metabolic inhibitors such as DNP and cyanide. How- 

 ever, metabolic inhibitors do not have marked 



effects on Na+ efflux in other tissues (cf. 7, 46). c) 

 Metabolic inhibitors produce a decrease in the K+ 

 influx about equal to the decrease in Na"*" efflux, but 

 Na+ influx and K+ efflux are not greatly affected, d) 

 Removal of K+ from the bathing solution reduces 

 Na+ efflux by about two-thirds. This is also true of 

 frog skeletal muscle (86). e) Na+ efflux and K+ 

 influx are temperature sensitive, having Qio's of 3 to 

 4. The opposite fluxes have low Qio's. All these find- 

 ings indicate an active Na"*" for K+ exchange process 

 dependent upon a supply of metabolic energy. Cou- 

 pling is suggested by the parallel changes in Na"*" 

 efflux and K+ influx with temperature and inhibition, 

 and by the marked reduction in Na"*" efflux when 

 [K+Jo is reduced to zero. Evidence for a cellular 

 energy requirement is the great sensitivity of the 

 active fluxes to low temperature and metabolic 

 inhibitors (cf 7). Both a lowering of temperature and 

 metabolic blockade reduce these fluxes because 

 they decrease the rate at which energy can be sup- 

 plied. Although substitution of Li+ for Na+ does not 

 abolish excitability, Li+ is not carried by the Na+ 

 pump in appreciable quantities (86). Information on 

 the various passive and active transport processes in 

 many different tissues is the objective of intense re- 

 search effort at present (lOo). 



Evidently the operation of a metabolically chiven 

 Na+-K+ pump is sufficient to maintain the low 

 [Na+Ji and the high [K+]i, Na+ being ejected and K+ 

 taken up as rapidly, on the average, as they enter and 

 leave. In the steady state, the active fluxes of Na+ and 

 K+ must be just equal and opposite to the flow of 

 these ions down their electrochemical gradients. It is 

 well established that nerve and skeletal muscle gain 

 Na+ and lose K+ during acti\ity (cf 53, 54). Since 

 cardiac cells are rhythmically active, it must be sup- 

 posed that they are in a steady state where the in- 

 creased passive fluxes of acti\ity are equalled by an 

 increased rate of Na+-K+ pumping so that internal 

 concentrations are not changing. 



As mentioned above, the efflux of Na+ from frog 

 skeletal muscle varies with the cube of [Na+]i for 

 sufficiendy low [Na+Ji, so there is no difficulty in 

 explaining the maintenance of the ionic distributions 

 in active cardiac muscle if its Na^-K* pump is similar 

 to that in .skeletal muscle. If this is true, the [Na+]i 

 should be somewhat higher in cardiac tissues than in 

 skeletal muscle. Experimentally, [Na+]i is 8 /imoles/ 

 cm' in skeletal muscle (85) and about 18 Mmoles 'cm^ 

 in cardiac muscle (51, 81). 



