Lipophilicity and pharmacodynamics of cardiotonic steroids in guinea-pig isolated heart muscle preparations.

1. The inhibitory potency of cardiotonic steroids on myocardial Na+-K+-ATPase increases with increasing lipophilicity. Employing the inotropic action on guinea-pig isolated left atria, the relationship between lipophilicity, chemical structure and the pharmacodynamic properties of cardiac glycosides was further examined. Nineteen digitoxigenin- and digoxigenin-derivatives, whose lipophilic nature and inhibitory effects on the myocardial Na+-K+-ATPase have been previously investigated, were tested. 2. All steroids exhibited positive inotropic effects which varied with the lipophilicity of these drugs. The dependence of the relationship between these two parameters on structural transformations of the steroids showed qualitatively very close parallelism to that between lipophilicity and their inhibitory effects on myocardial Na+-K+-ATPase. 3. The positive inotropic effects and the inhibitory effects on myocardial Na+-K+-ATPase also correlated very well, exhibiting similar patterns in their respective correlations with the individual lipophilicity parameters. 4. It is inferred that (a) the positive inotropic effects of the cardiac glycosides vary with their lipophilicity, exhibiting trends similar to those shown for their inhibitory effects on myocardial Na+-K+-ATPase, (b) this interdependence is secondary to the influence of structural changes, particularly on the steroid nucleus, and (c) both the lipophilic nature and pharmacodynamic behaviour of the cardiac glycosides almost exclusively depend on the steroid nucleus itself.