i6o 



HANDBOOK OF PHYSIOLOGY 



CIRCULATION I 



the membrane potential will be much lower, even 

 though the pump is efficient enough to maintain large 

 concentration differences of sodium and potassium on 

 each side of the cell membrane. This appears to be 

 the case in the erythrocyte (142). Conversely, a de- 

 crease in b will cause the membrane potential to 

 approach even more closely the equilibrium potential 

 for a potassium electrode. For a detailed discussion 

 of these subjects the reader is referred to references 

 12, 28, 142, 143, 313 and also the chapter in this vol- 

 ume by Woodbury. 



The inward current represented by the spike of the 

 action potential is thought to be carried by .sodium 

 ions which enter the cell because of a sudden increase 

 in membrane sodium permeability associated with 

 excitation. Repolarization must involve a movement 

 of ionic charge in the opposite direction — perhaps loss 

 of cellular potassium ion, uptake of chloride ion, or 

 both. The cell at this point has gained sodium and lost 

 potassium, and active transport of one or both ions is 

 required to restore the original conditions. 



It follows, then, that resting muscle in the steady 

 state should have measurable fluxes of sodium and 

 potassium across the cell membrane, which should in- 

 crease during activity. It has been shown by inde- 

 pendent methods that potassium efflu.x of amphibian 

 ventricle increases greatly with electrical stimulation. 

 Thus, Wilde el al. (325) showed a phasic increase in 

 the efflux of radioactive potassium from a cooled 

 turtle heart which corresponded in time to the T wave 

 of the electrocardiogram. Their elegant technique in- 

 volved the continuous collection of coronary sinus 

 effluent on a moving strip of filter paper, and had 

 enough sensiti\ity and time resolution to associate 

 the increased K efflux with the T wave. (The contrac- 

 tion cycle was very slow, the length of the T wave 

 itself being of the order of i sec.) The potassium re- 

 leased by the turtle heart under these conditions was 

 45 pmoles per cm- per beat. Hajdu (110) calculated 

 the amount of K released during the contraction of 

 isolated digitalized frog ventricle by measuring the 

 increase in bathing fluid potassium which occurred 

 over the course of 30 contractions. According to his 

 view, digitalization should have prevented any 

 re-entry of potassium lost from the cells during this 

 period. The resting K efflux was extremely small, 

 and the increase per contraction was 20 pmoles per 

 cm.- Both of these values are larger than the flux for 

 nerve which is in the range of 2-5 pmoles per cm- 

 per impulse, but this is hardly surprising considering 

 the differences in the tissues, notably the time course 

 of repolarization. Quantitative data on K fluxes in 

 mainmalian hearts have been more difficult to 



obtain, and there are no results based on either of 

 the experimental approaches mentioned above. 

 The available information is based on analyses of 

 K^'- efflux and influx cur\es (235, 236, 335) which the 

 authors consider can provide only approximate data 

 because of some intrinsic error in the kinetic analysis 

 (335) or nonexponential time course of the flu.x 

 curves (235, 236). Despite these uncertainties the 

 data show that K flux increases with increasing 

 heart rate, which confirms the basic finding on the 

 amphibian hearts. The resting potassium flux in 

 these mammalian tissues appears to be rather high. 

 This is not necessarily due to passive leakage out of 

 the cell with re-entry accomplished by active trans- 

 port, but may be only exchange diffusion. There is as 

 yet no evidence on this point. 



Analysis of sodium flux as a function of cardiac 

 activity has been successfully carried out for an 

 in situ dog heart preparation perfused with freshly 

 collected arterial blood (53). The hearts were loaded 

 with Na-^ and an efflux curve was obtained. Heart 

 rate was increased by electrical stimulation, decreased 

 by cooling the right atrium, and the results clearly 

 show a linear increase in sodiimt flux with increasing 

 heart rate, the sodium exchange per beat being 0.04 

 meq per kg heart tissue. Extrapolation of the sodium 

 flux heart rate cur\e to zero shows that the sodium 

 flux is close to zero at o heart rate. 



Further discussion of ion fluxes and heart rate can 

 be found in section vi. 



Potassium and Cardiac Excitability 



The effects of alterations in the concentration of 

 extracellular potassium on excitability are probably 

 secondary to the resulting changes in resting mem- 

 brane potential. The relationship between cardiac 

 resting membrane potential and extracellular potas- 

 sium concentration is linear, with deviations occurring 

 onlv at levels of potassium concentration below 

 about 10 mM per liter (38, 149, 200). [Hoffman & 

 Suckling (149) found that not only high [K]o but 

 also very low [K]„ below 0.48 mM per liter caused 

 depolarization of dog Purkinje fibers, but the latter 

 finding has not been observed in frog skeletal (4) or 

 cardiac (200) muscle.]' 



' The changes in resting potential caused by alterations in 

 potassium concentration which have been described by 

 Hoffman & Suckling (149) for Purkinje fibers as well as heart 

 muscle can be altered by alterations in the concentration of 

 calcium. The depolarization caused by increases in po- 

 tassium concentration can be reversed by increasing calcium 

 concentration. Likewise the depolarization associated with very 



