246 



HANDBOOK OF PHYSIOLOGY 



CIRCULATION I 



If it is assumed that the permeabiHty ratios remain 

 constant this equation accurately predicts the effects 

 of changes in [K+]o on 6 in a number of tissues (52, 63) 

 but see (i) for a case where the equation does not 

 apply and the assumptions are not true. Fitting 

 experimental data to this equation is one way of 

 estimating permeability ratios. Since Pk is normally 

 much greater than Px,, and [Cl~] \ is quite low, it can 

 be seen that at high values of [K+]o the other terms in 

 the numerator become negligible and £ will change 

 as rapidly as £k. At a normal [K+]o the other terms 

 are prominent and the change in voltage with 

 [K+Jo becomes quite small. The finding that when 

 [K+]o is high the membrane behaves as though it 

 were permeable only to K"*", i.e., as a potassium elec- 

 trode, has been frequently interpreted to indicate that 

 the resting potential arises from the K+ concentration 

 gradient and a membrane selectively permeable to 

 K"*". However, even if K"*" were equilibrated across the 

 membrane, there is no way of distinguishing a priori 

 whether the membrane potential arises from a pre- 

 existing K+ distribution or the K+ distribution arises 

 from a pre-existing potential as the Cl^ distribution 

 does. Actually, since the high [K+]i is the result of 

 active Na+-K+ transport and S arises because Pxa < 

 Pk, both possibilities are irrelevant. 



THE ACTIVE CELL MEMBRANE 



In the preceding description of the properties of the 

 resting cell membrane it was assumed that membrane 

 ionic permeabilities are invariant in time, although 

 they may vary somewhat with membrane voltage. 

 In contrast, the membrane action potential is gener- 

 ated by a characteristic sequence of rapid changes in 

 membrane permeability which are markedly depend- 

 ent on voltage. In fact, the action potential is cur- 

 rently "explained" in terms of these changes in 

 permeability since the underlying membrane mecha- 

 nisms are not known. The sequence of the permeabil- 

 ity changes during the action potential in the squid 

 giant axon has been described in quantitative detail 

 by Hodgkin & Huxley (60). Unfortunately, a similar 

 description of activity in cardiac muscle cannot be 

 given since the requisite data are not available, but 

 they do suggest that the changes in permeability 

 during the rising phase are much the same as those 

 in squid giant axons. Hence, a brief description of the 

 known permeability changes in giant axon mem- 

 branes is a useful preface to the study of the changes 

 in membrane permeability which may occur in heart 



muscle. These changes in .squid axons have been re- 

 cently reviewed by Hodgkin (53). 



The rising phase of the action potential in most 

 excitable tissue — including heart — is normally brought 

 about by a large increase in Psa- An increase in 

 Pnu leads to an increased net flow of Na+ into the 

 cell, down its electrochemical gradient. This net 

 entry of positive charges neutralizes the negative 

 charges stored against the inside of the membrane 

 and thus depolarizes it, i.e., reduces the magnitude 

 of the potential.'' If the increase in Pn„ is large enough, 

 the membrane charge will reverse, S approaching 

 Snb- The depolarization expected from an increase in 

 Pnq can be calculated from equation 6. In turn, 

 depolarization increases Px„, i.e., a reduction in mem- 

 brane potential causes a specific increase in Pxa. This 

 is a special property of the excitable membrane. Thus, 

 if S^a — S is greater than zero, i.e., if the Na+ electro- 

 chemical gradient drives Na+ inward, then depolariza- 

 tion may be spontaneous. 



Hodgkin (52) diagrams this regenerative sequence 

 as follows: 



'Increase in Na+ 

 permeability 



Depolarization 

 of membrane 



Entry of Na+ 

 provided Es^ — £ > o 



This depolarization-induced increase in Pn.t is not 

 maintained. Even if 8 is held constant near zero, Na"*" 

 current quickly falls to low values owing to a fall in 

 Pns. This time-dependent decrease in Pn., could bring 

 about the beginning of the recovery or repolarization 

 phase of the action potential alone, since K"*" and Cl~ 

 ions moving down their gradients would recharge 

 the membrane to the resting level at a rate deter- 

 mined by the membrane time constant. In squid 



* A charged capacitor is frequently said to be polarized. 

 Thus, a reduction in resting membrane charge is called "de- 

 polarization" (more accurately but confusingly, "hypopolari- 

 zation") and an increase "hyperpolarization." The rising phase 

 of the action potential is frequently called the depolarization 

 phase or simply depolarization. However, strictly speaking, 

 the membrane is depolarizing only until the potential passes 

 through zero. Thereafter, it is hyperpolarizing in the opposite 

 sense. The phrase "a reduction in S" should refer to hyper- 

 polarization, i.e., £ becoming more negative and thus de- 

 creasing; however, in common usage, "a reduction in £" 

 means depolarization, i.e., the phrase refers to the absolute 

 value of £, (|£|). This usage generally will be followed here, 

 but in cases where the intent is not clear from context, ad- 

 ditional specification will be given. 



