Cardiac glycosides with different effects in the heart

Remarkable differences exist between the effects of different cardiac glycosides (native and semi-synthetic) with respect to the affinity and to the magnitude of inotropic responses and their time courses. At glycoside concentrations which lead to identical Na-K-ATPase inhibitions, the inotropic responses vary widely. This finding contradicts the hypothesis that the increase of contractile force is the consequence of an ATPase inhibition and causally related to it. We propose the hypothesis that the inhibition of ATPase and the inotropic stimulation provoked by cardiac glycosides are two parallel events, not causally related but both mediated by the same receptor. The inhibition of the Na-K-ATPase is the consequence of the occupation and thus proportional to the concentration of the glycoside-ATPase complexes. In contrast, the inotropic response is determined by the frequency of glycoside-ATPase-interactions. Glycosides which possess high association and dissociation rate constants will interact with the ATPase with high frequencies and thus will evoke larger inotropic responses at a given ATPase inhibition than glycosides with low turnover rates.