CARDIAC MUSCLE CONTRACTILITV 



187 



sides could act in the absence of external calcium. 

 This view was first stated by Mandelstamm (205), 

 who stated that in a calcium-free medium the glyco- 

 side effect was still detectable, causing an increase in 

 contractile force, a plateau of tension, a prolongation 

 of the total duration of contraction, and even con- 

 tracture. Of course the fact that Mandelstamm ob- 

 tained muscle twitches showed that the bathing fluid 

 was not completely free of calcium. More helpful 

 were the in\estigations which showed a difference in 

 speed of onset of calcium and digitalis actions on 

 contractilit\- (77, 224). Nyiri & DuBois (224) expressed 

 their conclusions as follows: "The digitalis action, 

 therefore, takes place in the regular way and at the 

 regular speed in the presence or absence of calcium. 

 In the absence of this ion, however, we do not see the 

 effect because the heart muscle has lost its inotropic 

 propertN'. At anv time that we re-establish the con- 

 tractility of the muscle fiber in the course of the 

 digitalis poisoning, the effect of the corresponding 

 time appears." In other words, since it appears that 

 the steady progression of glycoside action can occur 

 in the absence of external calcium, the mechanism of 

 action cannot be to cause directly a net gain of intra- 

 cellular calcium. Even in these experiments there may 

 have been traces of calcium in the perfusion medium 

 due to contaminating amounts in other salts or in the 

 glycoside preparations. When care is taken to exclude 

 ionic calcium from the perfusion fluid and the glyco- 

 side preparation by addition of EDTA, toxic concen- 

 trations of glycosides have no detectable effect (113), 

 but addition of calcium causes immediate contracture 

 (unpublished observations). This indicates that the 

 primary action of glycosides on the muscle cell, which 

 normally is cumulative during the first 10 min of ex- 

 posure, occurs in the virtual absence of external cal- 

 cium ion, the positive inotropic action becoming 

 apparent immediately on the addition of calcium. The 

 same conclusion can be drawn from the work of 

 Caviezel & Wilbrandt (48) who showed that if one 

 allows for the inotropic action of calcium in the ab- 

 sence of digitalis, variations in the concentration of 

 calcium have no effect on the activity of cardiac gly- 

 cosides on heart muscle contractility. The effect of the 

 glycosides in inhibiting transmembrane potassium 

 transport in red blood cells (199) and skeletal muscle 

 (329) is likewise unaffected by variations in calcium 

 concentration. The evidence reviewed up to this point 

 shows that the primary action of digitalis on heart 

 muscle cannot possibly involve the calcium ion, but 

 it does not rule out a primary action that causes some 

 change within the fiber, as a result of which calcium 



accumulates. Such a change could de\elop in the ab- 

 sence of calcium, but one must postulate a capacity 

 for the glycoside-treated cell to take up calcium ex- 

 tremely rapidly in view of the immediate effects ob- 

 served on shifting from a calcium-free to a normal 

 perfusion medium [unpublished observations and 

 (224)]. 



It is probable that the glycosides have no direct 

 effect on calcium fluxes in heart muscle. It has been 

 reported that Ca''° influx is unchanged by nontoxic 

 doses of glycosides (125, 296); the diminution of efflux 

 oijserved in digitalized frog heart was at a contracture- 

 causing dose (323). The changes observed with con- 

 tracture-causing concentrations of ghcosides (125, 

 296, 323) are probably secondary to other cellular 

 alterations. 



Membrane Potential 



The effects of digitalis on the electrical exents of the 

 cardiac cycle appear to be as follows. Initially an in- 

 crease in the magnitude of the spike is sometimes ob- 

 served (339). This change is transient, and is followed 

 by a decrease in spike amplitude. Thus, normallv, the 

 spike describes a change in potential from —90 mv 

 to a positive value of about 30 mv, whereas in the 

 presence of toxic concentrations of glycosides the 

 spike decreases to the point where the "positixe o\'er- 

 shoot" disappears and even the zero potential level is 

 no longer reached (56, 339). Dudel & Trautwein (66) 

 have found that the glycosides cause a diminution in 

 the rate of rise of the action potential spike. The most 

 marked effects of the glycosides, however, are on the 

 repolarization phase. Following a transient increase 

 in the total duration of the action potential there is 

 marked shortening, due mostly to a decrease in the 

 time taken for repolarization (66, 339). 



The meaning of these findings in terms of cellular 

 ion movements is not known at this time, but it is 

 perhaps worth considering them in the light of a 

 hypothesis outlined by Cranefield & Hoffman (59). 

 As a result of the depolarization of the cell membrane, 

 the outflow of potassium would be expected to increase 

 since the ion is no longer held back by a large intra- 

 cellular electronegativity. However, the membrane 

 does not allow completely free diffusion of K+, and so 

 efflux is still comparatively slow during the plateau 

 (phase 2). The outflow is sufficient, however, to cause 

 the accumulation of some K+ at the extracellular sur- 

 face of the membrane and this by some mechanism 

 increases Pk which starts the rapid K+ outflow of phase 



