[70 



HANDBOOK OF PHYSIOLOGY 



CIRCULATION I 



calcium, alterations in the state of these calcium 

 complexes may influence certain of the factors 

 mentioned above. In our present state of knowledge 

 we can do no more than enumerate the calcium flux 

 changes that have been observed, and it will remain 

 for future investigators to determine the relationship 

 of these changes to the contractile process. Calcium 

 influx is influenced by the following interventions. 



/) Cell membrane depolarization. Depolarization of 

 excitable tissue membranes by high concentrations 

 of potassium is associated with increased influx of 

 calcium (i6, 146, 221). This has been observed in 

 frog heart, frog sartorius muscle, and squid nerve. 

 The occurrence in nerve as well as in muscle obviously 

 eliminates contracture as the cause of the increased 

 influx. Since the electrical gradient in the depolarized 

 state is less favorable for calcium influx, it would 

 appear likely that increased membrane permeability 

 for calcium occurs under these conditions. 



-') Muscular contraction. Prolongation of muscular 

 contraction or production of contracture is asso- 

 ciated with increased calcium influx, and this is 

 independent of the membrane potential, since it 

 may occur in even potassium-free solutions in whicii 

 the membrane is hypcrpolarized. Such results have 

 been reported with frog heart contracture produced 

 by ouabain (296), potassium-free bathing fluid 

 (296), and sodium-free bathing fluid (221). Increased 

 calcium influx has also been observed in frog sartorius 

 when nitrate ion replaces chloride as the major 

 anion in frog Ringer .solution. Under these conditions, 

 associated with an increased twitch tension due to a 

 prolongation of the active state (140, 160), there is 

 a 60 per cent increase in calcium influx. Since nitrate 

 ion does not alter the calcium influx of the unstimu- 

 lated mu.scle, the increased flux is clearly related to 

 the nitrate-induced prolongation of the active state 

 (16). Such calcium changes in cardiac tissue might 

 not be expected, since the reaction of i.solated toad 

 heart to nitrate is a decrease in contractility and 

 therefore apparently active state duration is not 

 increased (218). 



2) Ionic composition of bathing fluid. Hodgkin & 

 Keynes (146) have found that the calcium influx 

 in the case of the scjuid axon is greater in magnesium- 

 free solution than in normal sea water. Niedergerke 

 (221) believes that calcium moves into the cell in 

 combination with an anionic carrier, and that 

 sodium competes with calcium for the carrier. Thus, 

 he would explain the increased influx of calcium in 

 sodium-free solutions on this ijasis rather than on the 

 basis of the contracture wiiich occurs under these 



conditions. Experiments on nerve would therefore 

 be of interest in this regard. 



One can do no more than add to the list of unex- 

 plained phenomena the observations that calcium 

 efflux is diminished in low sodium or low potassium 

 solutions (222) and during ouabain-induced con- 

 tracture (323). 



Locus of Action of Calcuim on Contractility 



The previous discussion has dealt for the most 

 part with the subject of calcium and the cell mem- 

 brane. Even in this respect it has not been complete. 

 There is space to mention only in passing the fact 

 that alteration in external calcium concentration 

 may cause changes in the uptake of potassium by 

 the heart (238) and in the potassium content of the 

 heart (239). The calcium ion may be extremely 

 important in the structure of \arious membranes, 

 including those of red blood cells (21, 86, 203), 

 smooth muscle (29), and heart sarcosomes (51). 

 In addition to membrane efTects there are .several 

 intracellular loci at which calcium ion could aflJect 

 contractility. For example, it is known that micro- 

 injection of calcium chloride induces muscle contrac- 

 tion (131); calcium afl'ects the contractility of acto- 

 myosin threads (128); it affects ATPase activity (lo) 

 and is extremely important for the acti\it\ of relaxing 

 factor (13, 89, 163, 215). 



It is apparent, then, from studies on isolated 

 components of muscle that a variety of structures and 

 systems may be affected bv the calcium ion. Another 

 approach which may l)e more u.seful for tlic present 

 discussion is to consider what happens to intact 

 heart mu.scle depri\ed of calcium. On this basis there 

 appear to iae two sites sensitive to \ariations in 

 extracellular calcium. One is the cell membrane 

 itself. Although the cell membrane is resistant to 

 calcium deprivation (211, 297), it does become 

 inexcitable at very low concentrations of calcium 

 (78, 149). The second site is some calcium-sensiti\e 

 mechanism responsible for propagation of excitation 

 from the membrane to the contractile protein. This 

 site is apparentlv very sensitive to calcium since 

 variations in extracellular calcium concentration 

 ver\' rapidlv cause changes in twitch tension, and at 

 low calcium concentrations at which membrane 

 depolarization is still normal twitch tension chsap- 

 pears (297). There is certain evidence which suggests 

 that this site is located in a relatively superficial 

 region of the muscle cell. It was shown by Boehin 

 (19) that heart muscle which loses all contractility 



