The inotropic activity of digitalis genins is dependent upon C(17) side-group carbonyl oxygen position.
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, P less than 0.008. 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, P less than 0.003. 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.
D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D002415:Cats; D004073:Digitoxigenin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D004076:Digoxigenin / Q000494:pharmacology*; D004077:Digoxin / Q000031:analogs & derivatives*; D004305:Dose-Response Relationship, Drug; D009200:Myocardial Contraction / Q000187:drug effects*; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship; D014961:X-Ray Diffraction
D002316:Cardiotonic Agents; D004073:Digitoxigenin; C017227:20,22-dihydrodigitoxigenin; C043463:22-methylene-20,22-dihydrodigitoxigenin; D004077:Digoxin; D000254:Sodium-Potassium-Exchanging ATPase; D004076:Digoxigenin