CARDIAC MUSCLE CONTRACTILITY 



'79 



within 20 to 40 min after quinidine was removed 

 from the bathing medium. It would thus appear that 

 quinidine interferes with the passive loss of potassium 

 from the cell. The data on potassium influx are con- 

 flicting. Holland and Klein in their study observed 

 an increased potassium influx. On the other hand, 

 Karki (165) found that cold stored red blood cells, 

 when brought to a higher temperature, have a lower 

 than normal potassium uptake in the presence of 

 quinidine. 



EFFECTS OF EXTERNAL POTASSIUM CONCENTR.iiTION ON 



quiNiDiNE .'ACTION. The effect of quindinecan be coun- 

 teracted by decreasing the potassium concentration in 

 the extracellular fluid. This was shown by Armitage (8) 

 in experiments on perfused rabbit heart and isolated 

 rabbit atria. He found that the effects of 30 ^g per ml 

 of quinidine on both the rate and amplitude of the 

 heart beat could be reversed by lowering the 

 potassium concentration to i^ normal. Similar results 

 were reported by Holland (150), who showed that the 

 effect of quinidine on both twitch tension and effec- 

 tive refractory period of isolated rabbit atria could 

 be counteracted by lowering the pota.ssium. 



DISCUSSION. The increased cardiac potassium shown in 

 quinidine-treated rabbits (91), the abnormally low 

 loss of potassium from isolated cardiac tissue on rapid 

 stimulation (150), and the diminished potassium 

 efflux in the presence of quinidine all support the idea 

 that quinidine has an effect on the permeability of the 

 cell membrane to potassium. The diminution in the 

 rate of rise of the action potential in quinidine is quite 

 likely associated with a decrease in the influx of sodium 

 during depolarization. Since changes in resting mem- 

 brane potential have not been reported, the results 

 might suggest that quinidine has a peculiar effect on 

 the phasic changes in cell membrane permeability 

 that occur during activity. Thus, we have already 

 seen that the slowing of the rate of rise of the spike 

 could be interpreted in terms of a diminished cell 

 membrane permeability to sodium, \\hich normally 

 increases greatly during this period. Similarly, the 

 prolonged phase 3 (terminal repolarization phase) of 

 the action potential in the presence of quinidine and 

 the diminution of potassium effiux observed in stimu- 

 lated muscle might be explained in the terms that the 

 normal increase in permeability of the membrane to 

 potassium, that is thought to occur in phase 3, is in- 

 hibited in the presence of quinidine. 



There are not enough data at the present time to 

 explain the depressing action of quinidine on contrac- 



tility. Gertler's evidence that the intracellular con- 

 centration of potassium in quinidine-treated rabbit 

 hearts is increased provides a possible mechanism for 

 the decreased contractility, since it has been previously 

 noted that increased intracellular monovalent cation 

 content is associated in the frog heart with a decreased 

 contractility (see sections 11 and v). To date, no 

 correlation between the magnitude of the quinidine 

 effect and the change in intracellular potassium con- 

 centration has been made. The reversal of the quini- 

 dine action on contractility by immersing the tissue 

 in a low potassium medium can be explained by 

 assuming that the external pota.ssium concentration 

 is so low that the "potassium pump" is no longer 

 saturated, resulting in a diminution of potassium 

 influx and a consequent lowering of intracellular 

 potassium from the high levels characteristic of the 

 exposure to quinidine. The arguments for the idea 

 that stimulation is associated with the movement of 

 calcium from some superficial muscular site into the 

 cell interior have already been presented (see section 

 iv). It is possible that quinidine, with its apparent 

 action on membrane permeability, might cause 

 changes which would limit the diffusibility of the 

 calcium ion and depress contractility by this 

 mechanism. 



Effect of Qjiinidine on Metabolism 



Partly because of the effect of quinine on the 

 malaria parasite, the interest in the metabolic action 

 of quinidine has been great. A sampling of the litera- 

 ture may be found in references 135, 185, 300, and 

 310. These particular papers were chosen because 

 they are descriptions of experiments with heart tissue, 

 and the concentrations of drugs used were not more 

 than 10 to 20 times the therapeutic concentration of 

 the drug in plasma. Webb et al. (310) for example, in 

 studies on rat ventricle and auricle, found that in the 

 presence of quinidine endogenous oxygen uptake was 

 diminished, anaerobic glycolysis was diminished, but 

 there was no inhibition of the increased oxygen uptake 

 that occurred on the addition of various carbohydrate 

 substrates. On the other hand, Uyeki (300) found 

 that not only was endogenous oxygen uptake of rat 

 heart slices diminished but also the oxidation of 

 various carbohydrate substrates was inhibited. Uyeki 

 also found that calcium-activated ATPase activity 

 was diminished, and in homogenate studies he pre- 

 sented evidence that phosphorylation was also in- 

 hibited by quinidine at 5 X 10^%. The homogenate 



