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HANDBOOK OF PHYSIOLOGY ^ CIRCULATION I 



moval or inhibition of tlie normal pacemaker region 

 allows another nearby region with a slower intrinsic 

 rate to initiate impulses. 



In the pacemaker region an impulse is set up when 

 the slow diastolic depolarization reaches threshold 

 voltage. Generally speaking, the rate of rise and the 

 peak height of the action potential are less in a pace- 

 maker than in other parts of the heart. This reduction 

 can be attributed to the inacti\ation of rapidly avail- 

 able gNa during the slow diastolic depolarization, 

 i.e., the voltage is changing so slowly that gxa is 

 always near its steady-state value (127). Since the 

 threshold voltage is relatively fixed, the primary 

 determinant of the impulse discharge rate is the slope 

 of the prepotential — the steeper its slope, the faster 

 the rate. The slope of the prepotential is highly 

 dependent on external ion concentrations, tempera- 

 ture, and the concentrations of cholinergic and adre- 

 nergic substances. 



The membrane properties which lead to oscilla- 

 tion in heart cell potentials are not known precisely, 

 but these properties cannot be markedly different 

 from those of a quiescent cell membrane. Their 

 general nature follows from a study of oscillatory 

 behavior in the squid axon where the conductance 

 changes during activity are precisely known. Any 

 change that makes Sr about equal to the threshold 

 voltage is likely to produce oscillations. This con- 

 dition can be produced experimentally in squid 

 axon either by applying a steady outward current to 

 depolarize the membrane to threshold (16) or by 

 reducing the [Ca+^Jo to move the threshold toward 

 the resting potential (77). In the former case, the 

 sudden application of the current would quickly 

 depolarize the membrane voltage to threshold and 

 initiate an impulse. The lag in the fall of gK during 

 repolarization would carry S nearly to Sk for a short 

 time. Thereafter, as gK fell toward its resting level, 

 the membrane potential would fall with it and another 

 impulse would be initiated when threshold voltage 

 was again crossed. Within limits, the greater the 

 applied depolarizing current, the faster the rate of 

 impulse discharge. These qualitative considerations 

 of oscillatory behavior have been verified by solving 

 the Hodgkin-Huxley equations on an automatic 

 computer for different applied currents (16) and 

 different [Ca++]o's (77). Thus the oscillations occur 

 in squid axons because the repolarization process 

 carries the membrane potential past the resting level, 

 which is below the threshold potential. Oscillations 

 presumably could be obtained more naturally by 

 increasing resting gN„. An increased resting g^■a 



seems the most likely explanation of the oscillations 

 in cardiac tissue. It appears that the Brady-Wood- 

 bury model of repolarization could be made to oscil- 

 late l)y increasing the resting g.s;,. The oscillation 

 would result because the slow activation of gN„ follow- 

 ing repolarization would produce an actual increase 

 in gxa- The time course of 8eq in figure 22 during the 

 late third phase and slow diastolic depolarization 

 suggests that a combination of fast and slow activation 

 is contributing to actual g^^ to cause a fast and then 

 slow mo\'ement of Seq. 



Trautwein cS: Dudel (37, 120) found that membrane 

 slope conductance decreased during the slow diastolic 

 depolarization, in conformity with VVeidmann's meas- 

 urements (fig. 22). In addition, they calculated Sr 

 on the assumption that the fall in G is entirely due to 

 a fall in g^. This 8k was found to be invariant through- 

 out slow diastolic depolarization. 6k measured this 

 way agreed well with estimates of Sk made from a 

 study of the action of acetylcholine. Trautwein and 

 Dudel concluded that the pacemaker potential is 

 an after-hyperpolarization, the increased gK induced 

 by the preceding repolarization slowly decreasing 

 in time. This is the same mechanism as in squid giant 

 axon. However, it is difficult to tell whether the de- 

 crease in membrane voltage during slow diastolic 

 depolarization in heart is due to a decrease in gK or 

 vice versa. Hutter & Noble (75) have found that the 

 slope of the current-voltage relation of quiescent 

 cardiac muscle is the same over the voltage range of 

 the slow diastolic depolarization as Trautwein and 

 Dudel found during the pacemaker potential. Their 

 interpretation is rendered less likely as an explana- 

 tion of spontaneous activity by Hutter and Noble's 

 results since the fall in gK probably reflects the fall 

 in voltage, not a decay in time of gK- Nevertheless, 

 some time-dependent process must occur during the 

 diastolic depolarization and the possibilities seem to 

 be a decreasing gK, an increasing gM,,, or both. The 

 possibility that a changing gci contributes to the 

 pacemaker potential is eliminated because Cl~ re- 

 placement only transiently affects the rate (8, 73). 

 The decrease in G as the membrane depolarizes 

 probably indicates a time or voltage-dependent de- 

 crease in gKj in \'iew of the definition of G the finding 

 could indicate a voltage-dependent increase in gN,,, 

 but Trautwein and Dudel's finding that 8k is con- 

 stant assuming a variable gK appears to rule out this 

 possiijility. Noble (98) has modified the Hodgkin- 

 Huxlev equations so that solutions of them are re- 

 petiti\e heart-like action potentials. The pacemaker 



