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HANDBOOK OF PHYSIOLOGY 



CIRCULATION I 



the basis of indirect evidence that the potassium loss 

 was secondary to an increased efflux rather than to a 

 diminished influx. The action of veratrum in increas- 

 ing efflux appears to occur only during activity and is 

 probably associated with the prolonged depolariza- 

 tion and/or repetitive stimulation. 



In summary, the primary action of veratrine on 

 isolated cardiac tissue is on events following a normal 

 spike. Repolarization is greatly prolonged, and during 

 this phase repetitive small spikes may also occur. 

 These events are associated with an excessive loss of 

 cellular potassium which leads to an increased con- 

 tractile force and finally to slowed relaxation and 

 even contracture. The prolonged repolarization itself 

 may also contribute to the prolongation of mechanical 

 systole, although this phenomenon alone is not a.sso- 

 ciated with such an effect in all types of cardiac tissue. 

 Veratrum apparently has no effect on potassium 

 movements or contractilit\' of unstimulated cardiac 

 muscle. 



IX. DIGIT.^LIS 



Metabolism 



When a muscle is stimulated to contract and is 

 then allowed to return to its resting state, the event 

 may be viewed as two cyclic processes, one being the 

 shortening and lengthening of the contractile protein, 

 the other being the hydrolysis and subsequent re- 

 synthesis of a high energy phosphate compound (such 

 as ATP). The second cycle provides the energy for 

 the cyclic change in the protein, and it does not matter 

 for the argument how or at what point in the cycle 

 the phosphate bond energy is transferred to the con- 

 tractile protein. This energy-providing cycle has been 

 called '"energy liberation" by Wollenberger (333). 

 The maximum work obtainable from the operation 

 of the contractile protein cycle depends on many 

 factors which can be summed up as the ability of the 

 protein to utilize the available energy. In other words, 

 following the usage of Wollenberger, all the steps in 

 the energy cycle are part of the process called "energy 

 liberation"; whereas what the contractile protein 

 does with the energy made available to it is called 

 "energy utilization." 



The effect of cardiac glycosides on the failing heart 

 may be discussed by considering whether cardiac 

 failure in terms of the above frame of reference is 

 due to impairment of energy utilization or energy 

 liberation. In the case of the latter, the defect could 

 be in either ATP synthesis or ATP h\drol\sis. If .^TP 



synthesis were impaired, the concentration of ATP in 

 failing heart muscle should be below normal and the 

 therapeutic effect of the glycosides should be associ- 

 ated with a rise in the ATP concentration. Although 

 information on this point is not available for human 

 low output failure, in a variety of experimental con- 

 ditions characterized by an impaired cardiac 

 performance which improves with digitalis [failing 

 heart-lung preparation (332, 333), hypodynamic 

 guinea pig atrium (81)], ATP and CP (creatine phos- 

 phate) concentrations are not depressed and do not 

 rise on digitalization. (For exceptions see 20, 102.) 



If lieart failure were caused by a subnormal rate 

 of ATP hydrolysis, the therapeutic effect of the 

 glycosides should be associated witli a parallel in- 

 crease in ATP splitting (and also oxygen consumption, 

 assuming no oxygen debt) and obtainable muscle 

 work. Therefore the calculated efficiency (work out- 

 put/energy input) of the treated muscle would not 

 be diff"erent from that of the failing muscle. This is not 

 the case, Peters & Visscher (232) having found that 

 in the failing heart-lung preparation operating at 

 constant diastolic volume the administration of 

 cardiac glycosides caused increases of 63 to 153 per 

 cent in the mechanical efficiency. Qualitatively similar 

 results for human heart failure have been published 

 by Bing and co-workers (17). The defect in human 

 low output failure and in experimental conditions 

 characterized by a favorable response to digitalis 

 appears then to be an impairment not in energy 

 liberation but in the ability of the contractile system 

 to convert energy into useful work. The glycosides 

 increase the capacity of the contractile protein for 

 "energy utilization" which is reflected in an increased 

 mechanical efficiency; and any increase in oxygen 

 consumption associated with administration of the 

 glycosides is secondary to an increase in mechanical 

 work rather than to a primary action of the sjlycosides 

 on the "energy liberation" cycle. 



A large number of studies have been made to de- 

 termine whether cardiac glycosides have a demon- 

 strable effect on the metabolism of tissue slices or 

 homogenates. There is general agreement that the 

 glycosides do not affect oxygen consumption of mito- 

 chondria (183) or homogenates (88, 255, 258, 331, 

 332). The data on tissue slices are conflicting and 

 throw little light on the problem under discussion, 

 especially considering the normally depressed state of 

 muscle slices incubated in bicarbonate-free media 

 (59a, 247). Studies on the effect of glycosides on 

 radioactive phosphate turnover of muscle have been 

 compromised by the fact that extracellular inorganic 



