Cardiac glycosides: Prerequisites for the development of new cardiotonic compounds

Two prerequisites in a successful search for cardiac glycosides are the separability of the inotropicallyactive from the toxically-active component and knowledge of their structure-activity relationships and/or indispensible structural features. A number of papers show that toxic effects of heart glycosides are dependent upon inhibition of the Na+, K+-transport ATPase. This is not, however, the case with the inotropic effect, which has been shown not to be causally related to inhibition of the ATPase. Thus it is reasonable to assume that the search for selectively active compounds with the digitalis effect will be met with success. At present, however, there are no assumptions which can be made about the dependence of the pharmacological effect upon the structure. This would of course allow the prediction of structural details of the effective inotropic substance, and thus make possible its synthesis. Various studies have disproved the dogmas which have been adhered to for a long time. The structure-activity relationships are still obscure, although a host of individual phenomena are known. Some insight, however, results from those cases in which either the animal therapeutic index of this class of compounds is increased, or the frequency of arrhythmias is diminished. In elucidating such properies, the array of test methods used is of great importance. Methods, frequently applied today, such as the one determining the toxicity in the cat (Hatcher) or the ATPase test can easily lead to wrong conclusions unless they are used in conjunction with more revealing tests for inotropy.