l62 



HANDBOOK OF PHYSIOLOGY 



CIRCULATION I 



ventions are not due to changes in membrane poten- 

 tial (iio, 200). Not only twitch tension but also 

 contracture tension are similarly affected. It has 

 fallen to the lot of present-day physiologists to find 

 out at what locus and by what mechanisms such 

 alterations in extracellular cations act to produce 

 changes in contractility. The incompleteness of the 

 answer is attested to by the length of the following 

 discussion. 



One viewpoint, which has been advanced by 

 Hajdu (110), is that contractile force is affected by 

 an interaction between monovalent cations and 

 actomyosin, an interaction in which the contractile 

 protein does not distinguish between sodium and 

 potassium. The pertinent fact in support of this 

 idea is that depletion of intracellular monovalent 

 cation, either sodium or potassium, by an\ of several 

 means is associated with an increase in contractile 

 force. Loss of cellular potassium can be induced by 

 placing ventricular tissue in a potassium-free medium 

 (iio) by increasing stimulation frequency (see 

 section vi) or by digitalization (see section ix). 

 Cellular sodium loss occurs when a fraction of the 

 extracellular sodium chloride is replaced by a non- 

 penetrating sugar or ijy the chloride of a cation other 

 than sodium, such as lithium or choline. The re- 

 markable aspect of this phenomenon is that a very 

 small change in the intracellular ion content causes 

 a large change in contractility. For example, a loss 

 of 3 meq per kg of cellular potassium is a.ssociated 

 with a change from zero to 100 per cent contractile 

 force in the case of the isolated frog ventricle (iio). 

 Likewise, soaking of frog hearts in a solution con- 

 taining about one-fourth of the normal sodium 

 concentration is followed by a rise to maximum 

 contractility and a loss of about 10 meq per kg of 

 intracellular sodium ion. Another point of interest is 

 that changes in the concentration of intracellular 

 cation in the absence of an actual change in intra- 

 cellular content (e.g., water shifts caused by altera- 

 tions in the extracellular osmotic pres.sure) are not 

 associated with alterations in contractility. 



It should be emphasized that, since contractility 

 can be affected by changes in either intracellular 

 sodium or potassiimi, it cannot be the ratio of the 

 two ion concentrations which is important; but it is 

 rather the sum of the intracellular concentrations of 

 these two cations which seems to affect contractility 

 Furthermore, it would appear to be not the concen- 

 tration per se but the number of ions per contractile 

 protein unit which determines the contractile re- 

 sponse. According to this view, a reduction in the 

 total intracellular monovalent cation, whether 



accomplished by loss of either sodium or potassium, 

 should be associated with increased contractilit\ . 

 Two examples relating to mammalian hearts may be 

 cited. In one, contractility is enhanced by reducing 

 cellular sodium; in the other, by reducing cellular 

 potassium. Hercus et al. (134) base shown that the 

 soaking of isolated strips of rat right ventricle in 

 oxygenated Krebs bicarbonate solution results in a 

 loss of intracellular K and a gain of Na. There is 

 actually more sodium gained than potassium lost, 

 so that the total monovalent cation increases. If the 

 ti.ssue is shifted to a medium in which the sodium 

 concentration has been reduced, there is a sharp 

 drop in intracellular sodium concentration (134) and 

 a striking increase in contractile response (201). A 

 second example is provided by hearts from patients 

 in congesti\e failure. Like the rat hearts soaked in 

 Krebs solution, the concentration of potassium is 

 decreased and sodium is increased in these tissues 

 (43, 50, 123, 155, 208, 327). The therapeutic action of 

 digitalis, according to the view under consideration, 

 would be due to a decreased total intracellular cation 

 caused by a digitalfs-induced further decrease in the 

 already abnormally low cellular potassium (see 

 section ix and ref 1 13). 



Is there any other evidence to suggest that the 

 contractile protein can be affected by small changes 

 in monovalent cation concentration? Experiments on 

 both extracted actomyosin and on glycerinated heart 

 muscle fibers bear on this point. Szent-Gyorgyi (291) 

 has shown that extracted actomyosin may exist in 

 two states depending on the ATP and salt concen- 

 trations. At low ionic strength actomyosin exists as a 

 gel, whereas at higher salt concentrations it dissociates. 

 The addition of ATP causes syneresis of the gel (or 

 actual shortening of actomyosin artificial "fibers"), 

 but a \ery small increase in the KCl concentration, 

 by not more than 15 per cent, causes complete disso- 

 ciation of the actomxosin complex. It is thus apparent 

 that the physical state of extracted muscle protein 

 may be extremely sensitive to ionic strength changes 

 of the order produced in the intact cell. 



The glycerinated heart muscle fiber has also been 

 examined with respect to ion sensiti\ity (32, 129, 234, 

 293), but the results are conflicting. The glycerinated 

 fiber has been variously shown to a) suffer a great drop 

 in contractility with small increases in sodium con- 

 centration (234); /)) to show a great increase in rate 

 of relaxation on perfusion with sodium solutions (129); 

 and (-) to exhibit little or no sensitivity to changes in 

 concentrations of Na, K, H, or ATP (32). It is thus 

 possible to produce glycerinated fibers which contract 

 on the addition of ATP, but which exhibit e\cn less 



