CARDIAC MUSCLE CONTRACTILITY 



177 



t t 



FIG. 16. See text for description. 



in the section bounded by tlie two arrows the average 

 frequency was maintained by stimulating at a regular 

 rate of one half per sec, and following each regular 

 contraction with an extrasystole. It can be seen that 

 when the shift was made to the irregular frequency the 

 tension of the postextrasystolic contractions rose pro- 

 gressively to a plateau, and dropped back when regu- 

 lar stimulation was resumed. This rise in tension is 

 partly due to reverse staircase, since the interval be- 

 tween any extrasystole and the following contraction 

 is almost 2 sec rather than i sec as in the control 

 period, and the effect of the reverse staircase would 

 be to cause a greater tension after the longer rest 

 period. However, the rise in tension is progressive for 

 several beats, and the reverse staircase (i.e., recovery 

 of contractility) is not expected to change from beat to 

 beat. It seems likely, therefore, that an additional 

 factor contributes to the rise in tension, either the 

 postulated potassium shift of the Bowditch staircase 

 or a completely different phenomenon. In the former 

 case the progressive rise in the tension of the post- 

 extrasystolic contractions would be associated with a 

 pari passu drop in cellular potassium until a new steady 

 state level is reached. Since the average frequency re- 

 mains the same during the experiment, the develop- 

 ment of a lower steady state level of cell potassium 

 could occur only if potassium loss during an extrasys- 

 tole, following close on a normal beat, is greater than 

 during a regularly spaced contraction at the same 

 average frequency. No information on this aspect of 

 the Bowditch staircase is currently available, and so 

 the choice between an unknown or a potassium 

 mechanism cannot be made at this time. 



Hofmann believes that postextrasystolic potentia- 

 tion is not associated with potassium shifts, in part 

 because he could find no change in resting membrane 

 potential during the potentiation period, and he be- 

 lieves that a net efHux of potassium from the cell 

 should be associated with a temporary rise in the 

 potassium concentration immediately surrounding 

 the fiber large enough to cause a drop in the mem- 



brane potential. This assumption is certainly not sup- 

 ported by the finding of an unchanged membrane 

 potential during the administration of glycosides, 

 where it is well known that a considerable potassium 

 loss occurs. 



VII. qUINIDINE 



General 



Quinidine has dramatic eflPects on both the electri- 

 cal and contractile properties of heart muscle. The 

 electrical effect, as expressed by Love (195) in 1926, is 

 a lengthening of the effective refractory period of 

 heart muscle, that is to say, quinidine reduces the 

 maximum frequency at which atrial muscle can re- 

 spond to stimulation. The other well-known action of 

 quinidine is a reduction of the twitch tension of iso- 

 lated heart muscle preparations (150, 185, 216, 246). 

 The concentration of quinidine used in the studies on 

 contractility has generally been higher than the 

 plasma concentration achieved in the therapeutic 

 use of the drug, but in some cases {e.g., ref 150) the 

 concentration is about the same as that found in 

 certain instances of clinical toxicity due to quinidine 

 (9). The plasma concentration of quinidine at which 

 75 per cent of a series of patients with auricular 

 fibrillation reverted to a normal rhythm ranged from 

 4 to 9 mg per liter (282). Tissue concentrations may 

 be as much as lo-fold higher than plasma levels (312). 



Electrical Changes 



Intracellular microelectrode techniques have 

 yielded information which provides a basis for the 

 action of quinidine on refractory period and conduc- 

 tion. Weidmann, working with Purkinje fibers, showed 

 that in the presence of 10 /zg per ml quinidine sulfate 

 (a high dose, which was just short of causing conduc- 

 tion block) the rate of rise of the action potential and 

 the height of the spike were both diminished. A 

 "normal" response in the presence of quinidine could 

 be obtained if the membrane was hyperpolarized to a 

 resting potential of 120 mv before stimulation (314). 

 In contrast to calcium, which shifts the maximum rate 

 of rise versus resting potential plot to the left (see fig. 

 10), quinidine (as well as cocaine and procaine amide 

 in the case of the Purkinje fiber) shifts the curve in the 

 other direction. Johnson (156) also found that the 

 rate of rise of the action potential was diminished in 

 the presence of quinidine (3-4 Mg per ml), the effect 



