1 86 



HANDBOOK OF PHYSIOLOGY 



CIRCULATION I 



detect by tissue analysis. However, measurements of 

 potassium changes in the extracellular phase (re- 

 viewed in the first part of this section) leave little 

 doubt that therapeutic amounts of digitalis do cause 

 cellular potassium loss. 



Hajdu's analysis of changes in sodium, potassium, 

 and water of digitalized frog hearts, which was based 

 on both tissue and bathing fluid measurements, 

 showed that the tissue lost 13.7 ± 0.8 meq K per liter 

 of fiber water and gained 2.0 meq of Na. The cells 

 lost water along with potassium, such that the sum of 

 the intracellular concentrations of sodium and potas- 

 sium (meq liter fiber water) was not significantly 

 altered by the glycosides; but the amount of sodium 

 plus potassium expressed as meq per kg dry weight of 

 the cells had clearly decreased. Similar results for 

 digitalized dog heart have recently been reported by 

 Kyser et al. (182), who found a drop in cardiac 

 muscle potassium, but an actual rise in concentration 

 because of concomitant water loss. The increase in 

 contractility which occurs whenever the intracellular 

 monovalent cation content is diminished by any of 

 several means (see Section 11) led Hajdu (no) to 

 postulate that this diminution accounts for the glyco- 

 side positive inotropic effect. 



There is another kind of evidence which provides in- 

 direct support for the idea that the diminution in intra- 

 cellular potassium is causally related to the positive 

 inotropic action. Many years ago, Weizsacker (319) 

 showed in a group of carefully designed experiments 

 that the time of onsetof contracture, afterstrophanthin 

 was added to the medium perfusing a frog heart, de- 

 pended not on the duration of action of the drug but 

 on the number of contractions which occurred in the 

 presence of the drug. For example, at a frequency of 

 15 per min it required 30 min and 490 contractions 

 for systolic arrest, whereas at a frequency of 35 per 

 min toxicity was apparent in only 14 min after ap- 

 proximately the same number of contractions. Similar 

 conclusions have been reached by later workers (261, 

 322). Since increasing the contraction rate increases 

 efflux (see Section vi), it is clear that the onset of 

 the glycoside positive inotropic action occurs earlier 

 in a maneuver which hastens the net loss of cellular 

 potassium. 



GLYCOSIDES AND CALCIUM. Ever sincc Ringer's ob- 

 servation that increases in the bathing fluid concen- 

 tration of calcium strengthen tlie contraction of the 

 isolated frog heart, the generally similar action of 

 calcium and cardiac glycosides on cardiac contractil- 

 ity has been of great interest to investigators. It 



seemed that calcium enhanced the action of the glyco- 

 sides. For example, VVerschinin (320) in 1910 found 

 that systolic arrest of a perfused frog heart following 

 the addition of strophanthin was more complete and 

 appeared earlier when the calcium concentration of 

 the perfusion fluid was twice nonnal. Many workers 

 after this maintained that the activity of the glyco- 

 sides as reflected by toxicity in intact animals was en- 

 hanced by high serum calcium concentrations (26, 

 67, 97, 98, 190, 278). Were calcium and digitalis syner- 

 gistic in their action or were the above observations 

 simply due to the additive effect of two agents 

 each of which increased contractility by different 

 mechanisms? 



An early approach to this question was made by 

 Konschegg (177), who found that frog heart contrac- 

 tility which had been abolished in a calcium-free 

 medium was restored by strophanthin. He suggested 

 that cardiac glycosides could act in the absence of 

 calcium and could perhaps serve as a substitute for 

 calcium. Loewi (193) pursued the same experimental 

 approach, but used sodium oxalate in the medium in 

 order to be more certain of the absence of calcium 

 from the perfusion medium. Under these conditions 

 the heart exhibited no twitch tension, and the addition 

 of strophanthin caused contracture without restoring 

 the twitch. He recognized that there was still a small 

 amount of calcium ion in the bathing fluid, and be- 

 lieved that strophanthin acted by increasing the 

 sensitivity of the heart to calcium. 



Without entering into the controversy which cen- 

 tered around Loewi's contention, and recognizing 

 that even in the absence of glycosides heart muscle 

 contractility varies with changes in calcium, it may be 

 helpful to consider two possibilities. One is that 

 glycosides act by altering the intracellular concentra- 

 tion of calcium, thereby increasing contractility. The 

 other is that glycosides increase contractility through 

 a mechanism which does not involve a change in in- 

 tracellular calcium. In this case it still might be pos- 

 sible for glycoside effect on this mechanism to be al- 

 tered by variations in calcium. A choice between the 

 two main possibilities can be made then according to 

 whether or not intracellular calcium concentration is 

 changed by cardiac glycosides. For a positive inotropic 

 eflfect the expected intracellular change would be an 

 increase in calcium. If it could be shown that the 

 glycosides can act in the complete absence of external 

 calcium, this should constitute evidence that the ino- 

 tropic action is not due to an increase in intracellular jj 

 calcium. In at least three papers published several 

 years after Loewi's work it was claimed that the glyco- 



