The inotropic potencies of four digitalis genins were studied utilizing cat left atrial strips. The genin concentration required to induce a 50% increase of isometric tension (T50) was found to closely correlate with the degree of displacement (D) of the C(17) side-group carbonyl oxygen from the position of that atom in digitoxigenin. The line of regression was: log T50=0.54D-6.85, r2=0.98, P0.008. These observations were related to recently reported cat ventricular Na+, K+-ATPase inhibitory potencies of the same genins [expressed as 50% inhibitory (I50) concentrations]. I50 correlated strongly with T50: log I50=0.78 log T50-1.68, r2=0.99, P0.003. Thus, the activity of digitalis genins towards their receptor in intact cardiac tissue is closely related to genin carbonyl oxygen position as well as to Na+, K+-ATPase inhibitory activity. These results further support our earlier conclusions, based upon isolated Na+, K+-ATPase studies, that the digitalis genin C(17) side-group carbonyl oxygen position versus activity relationship is biologically relevant and may prove to be a useful unifying structural model in the further elucidation of the mechanism of digitalis-receptor interactions.
Bibliographical noteFunding Information:
This research was supported by the National Institutes of Health, DHHS (Grant HL 21457), and the Veterans Administration Medical Research Fund. The organization and analysis of the data base associated with this investigation were carried out in part with the use of the PROPHET system, a unique national resource sponsored by the NIH. Information about PROPHET, including how to apply for access, can be obtained from the Director, Chemical/Biological Information-Handling Program, Division of Research Resources, NIH, Bethesda, MD 20205. The technical assistance of the late Mr Fred Andrews and Mr Michael Barone and skillful manuscript preparation by Ms Mary Bougetz are gratefully acknowledged.
- C(17) side-group carbonyl oxygen position
- Digitalis genins