i8o 



HANDBOOK OF PHYSIOLOGY 



CIRCULATION I 



concentration of quinidine may bear some reasonable 

 relationship to the concentration of quinidine 

 achieved in tissue, if one accepts the data of VVegria & 

 Boyle (312) that tissue concentrations may be 10 times 

 that of the plasma. 



On the other hand, Lee (185) found that with 

 ciuinidine in a concentration of 3 X 10""%!, which was 

 sufficient to depress the contractility of cat papillary 

 muscle, there was no significant effect on the oxygen 

 consumption of cat heart slices. Hess & Haugaard 

 (135) in studies on rat heart slices and homogenates 

 found that oxygen uptake and glucose utilization 

 were depressed in the presence of 5 X io~% quini- 

 dine. They found, however, that procaine which has 

 somewhat similar actions to quinidine, at least on the 

 rate of rise of the action potential (314), had little 

 metabolic effect. 



It would appear then that although quinidine can 

 be shown to affect a variety of enzyme systems, there 

 remains a question as to whether the concentrations 

 required are reached in the therapeutic situation, and 

 whether the characteristic pharmacological action of 

 the drug is mediated by any of the enzymatic effects 

 observed. If, however, the effect of quinidine is pri- 

 marily on the phasic alterations in cell membrane 

 permeability to sodium and potassium which occur 

 during stimulation, the physicochemical mechanism 

 for this action still remains to be worked out. 



VIII. VERATRUM ALKALOIDS 



Summary of General Effects on Heart 



The veratrum alkaloids act on a wide variety of 

 nervous and muscular tissues. The result of these 

 actions in the whole animal is a complex series of 

 respiratory and cardiovascular responses (179). The 

 present section will be confined to the direct action of 

 the veratrum alkaloids on cardiac tissue. Reference 

 will be made to recent work on other types of tissue, 

 insofar as the results may throw light on the 

 mechanism of action of the veratrum alkaloids. 



The major effects of the veratrum alkaloids on the 

 heart are first a positive inotropic action and secondly 

 a striking alteration in certain of the electrical prop- 

 erties. Whereas the positive inotropic effect is fre- 

 quently masked in the whole animal because of re- 

 flex changes in heart rate and blood pressure, it is 

 readily observed in isolated heart tissue. The positive 

 inotropic effect of the veratrum alkaloids was dem- 

 onstrated early for amphibian heart, and was even 



more readily observed in hearts made hypodynamic 

 either by exposure to low calcium solutions or by 

 prolonged washing (179, p. 404). The positive 

 inotropic action of veratrine (a mixture of vera- 

 trum alkaloids) was also demonstrated in mam- 

 malian heart-lung preparations, more readily if the 

 heart was in failure (i 79). 



The effects of veratrine on the electrical properties 

 of the isolated heart include bradycardia, or oc- 

 casionally tachycardia at low dosages, and at larger 

 doses e.xtrasystoles which may finally end in fibrilla- 

 tion. Veratrine diminishes conduction \elocity and 

 may cause partial A-V block (179). It has been said 

 that veratrine may initiate spontaneous beating in 

 inactive strips of cardiac muscle (179). Such a vera- 

 trine response can be found in a publication of a 

 tracing of isotonic contractions registered by a strip of 

 left auricle from a guinea pig (253). In fact, this tissue 

 was not perfectly quiescent, and in the presence of 14 

 Hg per ml of veratrine no response was seen until a 

 spontaneous contraction occurred. Following this 

 single contraction, a series of beats occurred at high 

 frequency until finally the strip of tissue ended in 

 contracture. 



Electrophysiological Details 



EFFECT ON EXCITABILITY AND RELATED PHENOMENA. 



For conflicting early work on excitability and re- 

 fractory period of amphibian cardiac muscle, the 

 reader is referred to Krayer & Acheson's review (179, 

 p. 407). Information for mammalian tissue comes 

 from the work of Matsuda et al. (34, 209) on isolated 

 rat auricle and ventricle, and on dog ventricle. These 

 authors found that both the absolute refractory period 

 and the relative refractory period were increased in 

 the presence of veratrine. Like other authors (93) they 

 foimd that conduction in the A-V bundle was 

 markedly slowed. These workers point out (34) that 

 there is a period in the cardiac cycle corresponding 

 approximately to the relative refractory period in 

 which cardiac tissue may respond to electrical stimu- 

 lation of given strength and duration with multiple 

 beats or fibrillation. This so-called vulnerability ap- 

 pears to be increased in the presence of veratrine. 



MEMBRANE POTENTi.->iL CHANGES. In contrast to uerve 

 and skeletal muscle the effects of veratrine on the 

 action potential of cardiac muscle have not been 

 studied extensively. Matsuda et al. (209) have shown 

 that mammalian cardiac muscle in the presence of 

 veratrine may remain partially depolarized for a long 



