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IntroductionT h e digitalis-like cardiac glycosides exert a number of different actions on the mammalian heart in situ. Among the more important pharmacological effects of these compounds on the myocardium are the changes which they produce in the conduction system of the heart and in the factors associated with contraction of cardiac muscle. In therapeutic dosage, the glycosides c a u s e a slowing of impulse conduction in the heart and bring about increased force of cardiac systolic contraction accompanied by a decrease in diastolic size. T h e s e manifestations of pharmacological activity are present in both the human being and in the experimental animal, in both the normal state and in either experimentally induced cardiac dilatation or in the failing human heart in clinical cardiac decompensation. It is generally accepted that the greatest portion of the effects just outlined a r e due t o direct action of the drugs on the conduction bundle and myofibrils of the myocardium. Any property of a drug attributed t o its "direct action" on a given tissue could conceivably be associated with an effect of the drug on the metabolism of the cells composing the tissue. That such a possibility might b e responsible for some of the observed responses of the heart t o the cardiac glycosides was considered plausible from several viewpoints. T h e viewpoints considered involve speculation relative t o the possible effects of t h e s e compounds on three enzyme systems present in heart muscle.T h e work of Szent-Gyorgyi and his many co-workers and collaborators indicates that optimum levels of adenosine triphosphate (ATP) are necessary for optimal contraction of striated muscle.''2 T h e work of Rozsa3 indicates that, in the case of the active contractile elementof heart muscle (heart actomyosin), the s a m e necessity for an A T P optimum exists for optimal contraction. Rozsa a l s o showed that the actin and myosin of striated, smooth, and heart muscle of the rabbit a r e interchangeable, actin from one giving contractile actomyosin with t h e myosin of the other and vice versa. Further indication that cardiac muscle requires critical levels of A T P for optimal contraction can be drawn from the work of and of Burns and Cruckshank.' T h e s e investiga-*The authors gratefully acknowledge the support provided by a research grant-in-aid from the Chicago Heart Association. Chicago, 111. This grant has made this research possible. 379 380Annals New York Academy of Sciences tors demonstrated decreased efficiency of contraction of the heart under conditions (i.e., graded levels of iodoacetate poisoning) that a r e now known t o diminish A T P synthesis. Chang h a s also shown that during anoxia the mechanical efficiency of the rabbit heart is qualitatively correlated with the ATP level!bWork in the laboratories of t h i s institution directed by the late Professor A. G . Mulder (with the a s s i s t a n c e of the authors and others) h a s demonstrated a significant decrease in the A T P cbntent of in situ dog hearts in experim...

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