CARDIAC MUSCLE CONTRACTILITY 



185 



new steady state conditions are reached the trans- 

 membrane rate of potassium movement continues to 

 be depressed. 



It is thus seen that cardiac orlycosides depress the 

 active cell membrane mechanism responsible for the 

 uptake of potassium. This aspect of glycoside action 

 is not limited to muscle. Schatzman (264) has shown 

 that cardiac glycosides inhibit the potassium up- 

 take and sodium extrusion of previously cold-stored 

 red blood cells. Inhibition of red cell potassium influx 

 by glycosides has been confirmed by others (95, 96, 

 159, 162, 283, 290). A correlation between potency of 

 this effect and in vivo pharmacological activity has 

 been shown by Kahn (161). Sodium-potassium 

 exchange in the renal tubule also appears to be af- 

 fected by glycosides (226). Also interesting is the fact 

 that cardiac glycosides inhibit active transport of 

 certain anions. Chloride transport by the isolated bull- 

 frog gastric mucosa is diminished by strophanthidin 

 (55), and the uptake of iodide by slices of mammalian 

 thyroid tissue is profoundly inhibited by ouabain in 

 concentrations of about io~^m (330). The thyroid 

 effect seems to correspond to the in vivo pharmacologi- 

 cal activity of these compounds on the heart, since 

 dihydrodigoxin, for example, has not only low cardio- 

 tonic activity but also low potency with respect to 

 inhibition of iodide uptake. 



The broad tissue and ionic spectrum of glycoside 

 action suggest the possibility that the cellular mecha- 

 nism for transporting different ions consists of a part 

 which is common to many cells and an additional part 

 which confers ionic specificity to the system. The 

 cardiac glycosides, then, would appear to act on the 

 nonspecific part of the system. 



GLYcosiDE-POTASsiUM ANTAGONISM. It is generally ac- 

 cepted that potassium ions inhibit the action of digi- 

 talis, and it was suggested by Loewi (193) in 191 7 

 that intravenous administration of potassium salts 

 might abolish glycoside toxicity. This approach was 

 used in clinical medicine by later investigators (72, 

 259). Sampson et al. (259), for example, showed that 

 the ectopic beats caused by toxic doses of digitalis in 

 humans were abolished by the oral administration of 

 enough potassium acetate to cause a 10 to 30 per cent 

 rise in serum potassium concentration usually within 

 I hour. Conversely, with depletion of body potassium 

 signs of digitalis poisoning occurred at a lower drug 

 dosage than that characteristic of the potassium-re- 

 pleted state (196). Increasing extracellular potassium 

 concentration is associated with an increase in the 

 minimum lethal dose of glycosides in guinea pigs 



(130), with an inhibition of the effect of glycosides on 

 the rhythm of the embryonic duck heart (80), with 

 a diminution in toxicity for i.solated rabbit heart (11), 

 and with a decreased glycoside effectiveness in the 

 heart-lung preparation (40). In many of these cases 

 the potassium effect is on cardiac rhythm rather than 

 contractilit\-. If the rhythm is controlled, \ariations in 

 extracellular potassium concentration over the range 

 observed in clinical usage do not cause alterations in 

 the effect of the glycosides on contractility (84a, 187). 

 On the other hand, large changes in external potas- 

 sium concentration do inhibit the action of glycosides 

 (48) on contractility, and have also been shown to 

 reverse the characteristic action of the glycosides on 

 ion fluxes in red blood cells (96), kidney (226), and 

 thyroid (330). 



The nature of this potassium inhibition of glycoside 

 action is not understood. It appears that potassium 

 uptake by glycoside-treated tissues is enhanced bv 

 increasing extracellular potassium. This does not 

 occur in the absence of glycoside, suggesting that the 

 active transport system is normally "saturated" at 

 normal extracellular potassium concentrations and is 

 regulated by other factors probably related to intra- 

 cellular ionic composition. It is believed by some that 

 glycoside molecules and potassium ions compete for a 

 critical site on the membrane transport system and 

 that high concentrations of potassium can displace 

 the glycoside (96). There is no other working hy- 

 pothesis at the present time, but the possibility should 

 be noted that the glycoside-inhibited transport system 

 might be affected independently by potassium. 



CHANGES IN MUSCLE IONIC COMPOSITION CAUSED BY 

 GLYCOSIDES AND THEIR RELATIONSHIP TO THE POSITIVE 



INOTROPIC ACTION OF THE DRUG. The effects of digitalis 

 on ionic transmembrane flu.xes have been demon- 

 strated only recently, but many years before this was 

 known Calhoun & Harrison (44) showed that the 

 potassium concentration of hearts from dogs given 

 toxic doses of digitalis was diminished. Thev even 

 considered that this alteration in ionic composition 

 was the basis for the therapeutic action of the drug, 

 and suggested that digitalis "may act in such a way 

 as to readjust the ionic balance" of the failing heart. 

 During the ensuing years many workers measured 

 tissue potassium concentrations in an attempt to de- 

 termine whether therapeutic as well as toxic amounts 

 of glycoside caused a loss of potassium from the heart 

 (5. 27, 91. 108, 1 10, 151, 164, 225, 311, 337). The re- 

 sults were often conflicting, difficulties arising from 

 the fact that a small loss of potassium was not easy to 



