Absence of Digitalis-like Cardiac Effects in the Action Pattern of Several Simple Lactones. ∗

The cardiac glycosides are currently being subjected to investigative studies aimed at recognition of various relations of chemical structure and biological activity. Interest has centered on the lactone ring moiety and degradation of this component has been described as abolishing the typical digitalis effects(1). Further, various series of the simple lactones have been described from several laboratories as exhibiting positive inotropic effects when tested with cold-blooded hearts(1–10). At the same time, one of these reports by Chen et al.(3) presents evidence that a lactone producing digitalis-like effects on frog-heart preparations fails to exhibit such effects when tested on mammalian hearts. This observation made by electrocardiographic recordings in cats has been confirmed in the present report and has been extended by the application of a method determining the contractile force changes of mammalian hearts in situ. This same procedure of characterization has also been applied to other lactones previously described as exhibiting digitalis-like effects in frog-heart preparations. The essential objective of this study has been a determination of the suitability of the biologic characterization methods which may be used in the study of structure-activity relationships of this drug group.

Method. The contractile force of a segment of the right ventricle in open-chest dog preparations was measured according to procedures previously described(11). Factors influencing such determinations have been recently studied and described(12). Concomitant recordings of arterial pressures and electrocardiograph effects were made as before. Results obtained with lactones of the present study were compared against separate characterization studies which have been made under the same conditions with several cardiac glycosides, sympathomimetic amines, veratrine alkaloids and erythrophleum alkaloids. Each of these groups has been found to exhibit distinct and relatively consistent increments in contractile force when administered in favorable dose ranges.