CARDIAC MUSCLE CONTRACTILITY 



time following a normal spike, and during this period 

 repetitive brief spikes may occur. 



This type of phenomenon has been studied ex- 

 tensively in nerve and skeletal muscle (see for example 

 references 3, 74, 181, 269). The reader is referred to 

 figure 18 for terminology of the various components 

 of the action potential. The veratrine response in 

 these tissues is characterized frequently but not always 

 by the production of a large and prolonged negative 

 afterpotential. The question is whether the repetitive 

 firing which occurs in the presence of veratrine is 

 correlated with or caused by the size of the negative 

 afterpotential. In some instances a good correlation 

 has been obtained between the size of the negative 

 afterpotential and the occurrence of repetition (181). 

 In other cases no necessary correlation has been noted 

 (74). In some of the work of Shanes (269, 271) on the 

 squid axon it would appear that in the presence of 

 veratrine the normal oscillations of membrane po- 

 tential which occur following repolarization do not 

 become damped but, on the other hand, may pro- 

 gressively increase in amplitude to the point where 

 they become adequate as stimuli and initiate spikes. 

 It is clear that the factors invoked in the production of 

 repetitive activity are not yet fully understood, and 

 further discussion is beyond the scope of this review. 

 Suffice it to say that in certain tissues (such as some 

 of the nerve preparations studied) the oscillatory 

 phenomena in tine presence of veratrine are prominent 

 without a tremendously increased negative afterpo- 

 tential, whereas in the case of the mammalian heart 

 the striking feature is the delay in repolarization. 



Finally the work of Shanes et al. (274) on impedance 

 changes following the spike in squid nerve in the 

 presence of veratrine should be mentioned, since the 

 results ma\- provide further information on the mode 

 of action of the drug. These investigators found that 

 the negative afterpotential following the spike in the 

 squid axon is accompanied by an increase in measured 

 conductance. The cause of the conductance increase 

 could perhaps best be explained by an increase in the 

 permeability of the membrane to sodium ions, al- 

 though there was some objection to this becau,se the 

 quantitative relationships between the observed 

 change in conductance and the magnitude of the 

 negative afterpotential (3 mv) was considerably 

 different from the predicted value. 



Effects on Contractility and Ion Movements 



CONTRACTILITY. It was established early that the pro- 

 longation of the contractile response of striated muscle 



in the presence of veratrine was due to a tetanus 

 caused by the repetitive firing which occurred. Such 

 an explanation for the observed prolongation of systole 

 in cardiac tissue (179, p. 412) was not very palatable, 

 since cardiac muscle is said not to be capable of 

 tetanization. Whereas this may be true in the general 

 case, one may ask what happens to the mechanical 

 response of cardiac muscle if repolarization is delayed 

 for, say, several seconds. Rosenblueth et al. (251) gave 

 a categorical answer to this question as a result of 

 studies on turtle ventricle in veratrine. They found no 

 necessary correlation between mechanical and elec- 

 trical events in this tissue. They concluded that the 

 potential changes and the contraction were largely 

 independent and felt that whereas the spike triggered 

 the contraction process, the time course of contraction 

 was probably governed by factors other than the 

 potential changes. On the other hand, Kavaler (170) 

 has found in the case of mammalian ventricle that 

 prolongation of repolarization by a voltage clamp is 

 associated with prolongation of the contractile re- 

 sponse. It is interesting that whereas this is the case for 

 ventricular tissue, prolongation of depolarization in 

 the case of the atrium is not associated with a pro- 

 longed mechanical systole (171). We may conclude 

 then that at least in certain cases prolonged depolari- 

 zation may be associated with prolonged contractile 

 response. Another factor which quite likely contributes 

 to prolongation of mechanical systole has to do with 

 the loss of potassium from veratrinized cardiac muscle, 

 which is described in the next section. Suffice it to 

 say at this point that potassium loss from cardiac 

 muscle whether induced by digitalis, veratrine, or a 

 potassium-free bathing medium is associated with pro- 

 longed contraction because of slowed relaxation. The 

 positive inotropic effect caused by veratrine is pre- 

 sumably also due to the cellular changes associated 

 with the potassium lo.ss, as has been suggested in the 

 case of digitalis (see section ix). 



POTASSIUM MOVEMENTS. It was first shown by Szent- 

 Gyorgyi et al. (292) that stimulation of skeletal muscle 

 in the presence of veratrine was associated with a 

 large loss of potassium from the tissue. Similar results 

 were obtained by Shanes (270) for nerve, who found 

 that the net potassium lost from crab nerve during 

 stimulation in the presence of low concentrations of 

 veratrine (insufficient to induce a repetitive response 

 to stimulation) was almost twice the potassium lost in 

 the control preparation. Large potassium losses were 

 also observed in the case of cardiac tissue by Hajdu 

 (ill) and by Vick & Kahn (304) who concluded on 



