i66 



HANDBOOK OF PHYSIOLOGV 



CIRCULATION I 



plateau such as that seen in figure 1 1 at calcium 

 concentrations as high as lo min per liter. 



The speed with which calcium ions can increase 

 twitch tension has been shown beautifully by VVeid- 

 mann (316) in experiments on isolated turtle ventri- 

 cles. The turtle heart was perfused through the 

 coronary artery with a low calcium Ringer's solution 

 and was stimulated to beat once per minute in the 

 cold. By means of a second small catheter, which was 

 placed in the coronary artery cannula, it was possible 

 to inject a bolus of concentrated calcium chloride 

 over a period of 2.5 sec. The normal contraction 

 cycle of turtle ventricle at these low temperatures was 

 long enough so that the calcium could be injected 

 after the onset of contraction, but before the end of 

 the contraction cycle. The results of such experiments 

 show that calcium injected after the onset of con- 

 traction increases the twitch tension of that con- 

 traction. 



The effect of calcium ions can be seen not only in 

 a normal twitch but also in contractures caused, for 

 example, by high concentrations of potassium chloride. 

 Niedergerke (219) has shown that between o and 4 

 mM per liter calcium chloride the tension of strips of 

 frog ventricle in a potassium chloride contracture 

 increases with the concentration of calcium in the 

 bathing medium. The efl'ects of calcium on the 

 contractility of heart muscle are thus well docu- 

 mented but the mechanism of calcium action is not 

 understood at tlie present time. In the sections that 

 follow, an attempt will be made to summarize the 

 information in the literature that bears on this 

 question. Since the information in the case of heart 

 muscle is frequently meager or nonexistent, appro- 

 priate data from other tissues will be discussed. 



Calcium and the Electrical Properties 

 of Excitable Tissue 



The effects of increasing calcium in excitable 

 tissues have been studied at great length, and in 

 general it has been found that the effects include 



a) increase in current strength needed for stimulation, 



b) slowing of spontaneous rhythm, and c) block of 

 conduction of impulses (33). The effect of increased 

 calcium ion in decreasing irritability of amphibian 

 hearts was observed very early (for references, .see 103), 

 and was confirmed in the case of cat papillary muscle 

 by Greiner & Garb (103) in 1950. With the use of 

 microelcctrode techniques the basis for some of the 

 previously observed results has now been elucidated. 

 For example, Weidmann (314) has shown in the 

 case of Purkinje fibers that in increased calcium 



solutions the threshold potential is decreased. The 

 threshold potential in his experiments was the mem- 

 brane potential at which propagated depolarization 

 occurred in response to a 50 msec square pulse. 

 Similar results in a different preparation and with a 

 different experimental protocol were obtained bv 

 Frankenhaeuser & Hodgkin (79) in studies on giant 

 squid axons. They found, starting with fibers that 

 were hyperpolarized 41 mv above the usual resting 

 potential, that the higher the external calcium 

 concentration the greater was the depolarization 

 needed to achie\e peak sodium conductance. Since 

 sodium conductance must increase to a certain 

 critical level for propagated depolarization to occur, 

 these results also indicate that in high calcium a 

 greater depolarization is required before a propa- 

 gated impulse occurs (i.e., threshold potential is 

 lowered and the distance S in figure g is increased), 

 and thus excitability is diminished. By the same 

 token however, since the threshold potential is 

 lowered, the tissue following stimulation becomes 

 re-e.xcitable at a relatively early stage ol repolariza- 

 tion. Perhaps, this can explain the results of Grumbach 

 and co-workers (106) who noted that ventricular 

 fibrillation of isolated rabbit heart could be induced 

 by sudden increases in extracellular calcium concen- 

 tration. Comparable changes in dog heart had 

 previously been ob.served by Butcher et al. (42). An 

 alternative explanation for the arrhythmias that may 

 be seen with increased calcium which is fa\ored by 

 Brooks et al. (34, p. 298) is that the marked decrease of 

 threshold potential caused by the increased calcium 

 creates local crjnduction blocks thought to be favor- 

 able for the dcN'elopment of fibrillation. 



The effects of calcium ions on the rate of rise of 

 the action potential are very interesting. It has 

 already been noted that if the resting membrane 

 potential is lowered the rate of rise of the action 

 potential is likewise lowered. The effect of increasing 

 calcium is to shift the curve to the left along the 

 membrane potential axis [fig. 10 (79, 314)]. Franken- 

 haeuser and Hodgkin have pointed out that both 

 with respect to this phenomenon and to the effect on 

 threshold potential increasing calcium is equivalent 

 to hyperpolarizing the resting membrane. 



Some of the effects of calcium on the phases of the 

 action potential which follow the spike have been 

 studied by Hoffman & Suckling (149). Increasing 

 the calcium concentration in the bath of isolated 

 papillary muscle causes an increa.se in the speed of 

 the initial phase of repolarization (phase i ) which 

 occurs before the plateau (phase 2). Repolarization 

 continues without the delay characteristic of a 



