HANDBOOK OF PHYSIOLOGY ^- CIRCULATION I 



FIG. 1 7. Effect of quinidine on the relation between stimula- 

 tion frequency and rate of rise of the action potential. Open 

 circles: control. Closed circles: in 10 ;ug/ml quinidine sulfate. 

 [From Johnson & McKinnon (157).] 



FIG. 18. Diagram of nerve action potential. PP: positive 

 potential. NAP: negative afterpotential. PAP: positive after- 

 potential. [From Shanes (271).] 



on the height of the spike being variable. His experi- 

 ments were performed on guinea pig ventricular 

 mu.scle. Similar results were obtained by Vaughan 

 Williams (302, 303), using guinea pig atria and a 

 quinidine concentration of 9 /jg per ml. He observed 

 not only a decreased rate of rise of the AP and a 

 diminished spike height, but also noted that although 

 the beginning of repolarization was normal the termi- 

 nal phase was prolonged. Johnson & McKinnon (157) 

 in a careful study on guinea pig right ventricle, in 

 which results were based on a well-fixed microelec- 

 trode remaining in position throughout the course of 

 an experiment, found that the maximum rate of rise 

 of the action potential decreased with increasing fre- 

 quency of stimulation above a critical level. This rela- 

 tionship is shown in figure 17. It can also be seen in 

 this figure that in the presence of 10 yug per ml of 

 quinidine sulfate the decrease in the maximum rate of 

 rise in the action potential began to occur at lower 

 frequencies. 



Vaughan Williams (302) has pointed out that the 

 physiological studies discussed above provide some 

 insight into the mechanism of action of quinidine. As 

 stated earlier, a tissue will not respond to stimulation 

 with a propagated depolarization unless the rate of 

 change of the membrane potential induced by the 

 stimtilus is above a certain minimum. This rate de- 



pends on many factors, including the magnitude of 

 the resting potential. The higher the resting potential, 

 the higher the rate of rise of the action potential 

 (see fig. 10). Below a critical resting potential no 

 propagated action potential can be produced. Con- 

 sider, then, a muscle which has contracted and is re- 

 covering. The membrane has been depolarized and 

 must now repolarizc to a critical value before the 

 muscle can respond to another stimulus with a suffi- 

 ciently fast rate of rise of the action potential for a 

 propagated depolarization. But since quinidine slows 

 the rate of rise, the quinidine-treated muscle must 

 repolarize further than the normal before the muscle 

 can respond, and this of course means more time 

 elapses before the muscle is ready for another stimulus. 

 In addition, the tail of the repolarization phase in 

 quinidine is somewhat prolonged. Thus not only must 

 the repolarizing membrane reach a higher membrane 

 potential before a propagated response can occur in 

 quinidine, but the time taken for it to reach this level 

 is prolonged compared to the normal. These two 

 factors, then, combine to produce the prolongation of 

 the effective refractory period which occurs in the 

 presence of quinidine. The absolute refractory period, 

 on the other hand, that is the time interval from the 

 peak of the action potential to the point when a local 

 nonpropagated response can occur, is not prolonged 

 in quinidine, since the early phase of repolarization 

 does not appear to be affected by the drug in the con- 

 centrations used in the above studies. 



Effect of Qjiinidine on Ionic Concentration and 

 Fluxes in Muscle 



IONIC coNCENTR.\TiONS. Gertler et al. (91), in experi- 

 ments on rabbits, found that after o. 1 2 g of quinidine 

 gluconate twice daily for 5 days the intracellular 

 cardiac potassium concentration had increased from 

 108 to 124 meq per liter cell water (calculated on the 

 basis of chloride space measurements), and the intra- 

 cellular .sodium concentration had decreased from 

 13.6 to 6.8. Both changes were statistically significant. 

 Holland found that the net potassium loss from iso- 

 lated rabbit atria stimulated at 200 per min for 5 min 

 in low potassium Ringer's solution was 3.81 mM per 

 kg wet tissue for seven control atria, and 3.27 for fi\e 

 atria in 5 X io~^ m quinidine (150). 



IONIC FLUXES. Holland & Klein (152) showed that the 

 potassium efflu.x from rabbit atria after 20 min in 

 quinidine (concentration not stated) was decreased b\- 

 40 to 50 per cent, and ihat the flux returned to normal 



