Abstract

We have investigated the effect of chlorpromazine and aldosterone on the positive inotropic effect and the subcellular distribution of ³H-digoxin in isolated, electrically driven guinea-pig hearts. Both drugs decreased the positive inotropic effect of ³H-digoxin and the uptake of the drug by the microsomal fraction, whereas the total tissue uptake and the tissue/medium ratio of the radioactivity did not differ significantly from control. Because all measurements were made in the same experiments, we were able to show a significant correlation between the positive inotropic effect and the content of ³H-digoxin in a crude microsomal fraction, but not in the mitochondrial or nuclear fractions. A significant fraction of the bound drug was released into the supernatant when the microsomal pellet was shaken in Krebs' solution and recentrifuged. There was a greater correlation of the inotropic effect with the loosely bound drug than with the total microsomal binding; there was no correlation between contractility and the drug remaining in the microsomal pellet. Gel filtration of the supernatant showed that the drug was not bound to a macromolecule. We suggest that the digoxin taken up by the cell and bound loosely to a constituent of the microsomal fraction is responsible for the positive inotropic effect.