262 



HANDBOOK OF PHYSIOLOGY 



CIRCULATION I 



Weidmann's findings serve to establish the mode of 

 action of increased [K+]o in making cardiac muscle 

 inexcitable. Because Pk is relatively high, a sufficient 

 increase in [K+]o decreases fi until the amount of 

 readily available gxTj is reduced to a nonregenerative 

 level. Figure 18 shows superimposed recordings of 

 the action potentials of a frog ventricle perfused with 

 Ringer's solutions containing different [K+]o's. 

 As [K+]o increased the duration of the resting po- 

 tential and action potential progressively decreased 

 until, at a [K+Jo three times normal, excitability was 

 lost. Overshoot was progressively, but only mod- 

 erately, reduced by the increasing [K+Jo until just 

 before block. 



Repolarization 



The nature of the ionic conductance clianges under- 

 lying the prolonged repolarization process in cardiac 

 muscle is the largest outstanding problem in cardiac 

 electrophysiology immediately susceptible to experi- 

 mental attack. The experimental data a\ailable 

 are not sufficient to define uniquely the manner in 

 which gNa, gK, and gci (assuming that Na+, K+, 

 and Cl~ carry all the current as shown in fig. j^B) 

 vary during repolarization. Although no definite 

 conclusion about the mechanisms involved is possible, 

 a number uf attractive concepts can be excluded. 

 Throughout the following discussion it is assumed 

 that the ionic theory, suitably modified, can account 

 for tlie prolons;ed action potentials of cardiac muscle. 

 However, the necessary modifications cannot yet be 

 completely specified. 



It can be seen in figures i, i6.-l, 18, 19, 20, 21, 22, 

 and 25 that repolarization in cardiac tissue consists 

 of two or three distinct phases which blend into one 

 another. The first phase is the initial spike, which is 

 always present in Purkinje tissue (fig. 22) but which is 

 not prominent and is sometimes absent in other 

 cardiac tissues. A first phase appears in the frog 

 heart, in reduced [Na+]u (fig. \&A). The second phase 

 is the prolonged plateau on either side of the minimum 

 slope inflection point. The second phase grades 

 slowly into the third phase of rapid repolarization. 

 This nomenclature was introduced by L. A. Wood- 

 bury and co-workers (139) in 1951 and will be used 

 here for descriptive purposes. When all three phases 

 are present, their mid-points are at the successive 

 inflection points of the repolarization process and 

 their boundaries are at the peak of the action po- 

 tential and at the .succeeding points of maximum 

 curvature. It is noteworthv ihat tiic third inflection 



point occurs only about 15 mv above the resting 

 potential in the frog \entricle (cf. fig. 20C). Although 

 the shape and duration of the action potential varies 

 considerably among the various cardiac tissues, the 

 three phases are generally present. This fact leads to 

 the assumption that the underlying mechanisms are 

 much the same in all vertebrate hearts, varying only 

 quantitatively from animal to animal. Thus con- 

 clusions obtained from experiments on one type of 

 cardiac tissue are considered to be generally ap- 

 plicable to other cardiac tissues. 



During the second phase 8 and hence capacitative 

 current are negligibly small and S is about twice as 

 close to Sn-:, as it is to ^ 2(^01 + Sk) (table i ). There- 

 fore, during this period, i;-,;a niust be about twice as 

 great as gK + gci- It follows that during repolariza- 

 tion there must be a considerable period when g>ja 

 is elevated, (gn + gci) is depressed, or both. A 

 teleological argument suggests that gK probably 

 decreases during the plateau. Such a decrease would 

 reduce considerably the passive exchange of K"*" for 

 Na""" and thus reduce the load on the Na+-K+ pump. 

 This argument does not apply to Cl^ since it is not 

 actively transported and [Cl"]i distributes itself 

 so that the average net flux is zero. As mentioned 

 above, Sci must be considerably .smaller in magnitude 

 than the resting potential in a rhythmically active 

 heart. Thus the effects of Cl~ on the repolarization 

 process are to speed early repolarization when S > 

 8ci and to slow late repolarization when S < Sci — 

 the greater gci, the greater these effects. 



F.aiCTORS AFFECTING REPOLARIZATION. One of the 



most striking characteristics of cardiac action po- 

 tentials is the extreme variation of repolarization 

 with the ionic composition of the bathing medium 

 (3, 4, 8, 10, 13, 21, 25, 31, 35, 71, 73, 128, 130), 

 with stimulus rate (4, 10, 1 17), and with temperature 

 (23, 118, 121) in any one type of cardiac cell. The 

 variation between different cell types and between 

 species is ecjualK' striking (figs. i6.4, 19, 21, 22, and 

 25). The duration of the action potential in ner\e or 

 skeletal muscle varies slightly to moderately with 

 these same changes. As an example, the duration of 

 the action potential iXxv) of a frog ventricular cell 

 varies from about 1.5 sec at low stimulus rates to less 

 than 50 msec at high rates, a ratio of about 30 1 . 



The effects of variations in [Na+]o on txp are 

 shown in figure i6.^. As expected from the ionic 

 theor\', a decrease in [Na+]o reduces the size and 

 duration of the action potential. In the experiments 

 illustrated in figure i6.-l, Na+ was replaced by 



