Differential inactivation of inotropic and toxic digitalis receptors in ischemic dog heart. Molecular basis of the deleterious effects of digitalis.

When applied to ischemic hearts digitalis exhibits depressed inotropic effect and increased toxicity. The molecular basis of these effects was investigated at the level of the digitalis receptors characterized by Na,K-ATPase assays and [3H]ouabain-binding measurements. In sarcolemma obtained from dog hearts rendered ischemic for 15, 30, and 60 min (left anterior descending), two populations (high and low affinity) of digitalis receptors were detected. The apparent affinity (KD, 300 nM) and the binding capacity of the low-affinity sites (responsible for toxicity) remained constant and similar to those found in normal hearts. The KD value of the high-affinity sites, "responsible for inotropy," remained unchanged (2 nM), but the site number sharply decreased (up to 90%). These inotropic sites that account for 66% of the total binding in normals are gradually inactivated, as the duration of ischemia increases. This inactivation would occur in situ since it was detectable in homogenates and was not depressed by the isolation procedure per se. The loss of function of the inotropic sites and the increased contribution of the low-affinity toxic sites represent the setting of a new distribution of the digitalis receptors in the ischemic heart before reperfusion is instituted. This constitutes the molecular basis of the deleterious pharmacological effects observed with digitalis.