Influence of the Na-K-ATPase Activity Upon the Kinetics of Ouabain Binding to Cardiac Tissue

Abstract

Rate and degree of ouabain binding to isolated guinea pig atrial muscle depend on 1.) the concentration of the drug applied to the incubation medium, and 2.) the contraction frequency of the preparations. Either an increase of the drug concentration at a constant beat frequency or an increase of the beat frequency at a constant drug concentration enhances the rate of binding and the amount of ouabain bound at equilibrium conditions. The data may be explained as follows: 1.) At a given beat frequency and therewith a constant sodium load the ATPase-activity required for Na extrusion remains constant. This also implies that a constant concentration of that particular conformation exists, which is able to bind cardiac glycosides. Under this condition the binding kinetics of ouabain are solely governed by the drug concentration in the medium. 2.) At a given concentration of ouabain in the bath but a different frequency of contraction the Na-load and the ATPase-activity varies. Hence, the concentration of digitalis binding conformations is determined by the frequency. Under this condition the binding kinetics of ouabain in cardiac tissue appear to be determined by the frequency of contraction. At different beat frequencies different proportions of the total amount of ATPase molecules are required for the maintenance of Na-K-homeostasis. It is only the fraction which is not involved in the ion transport that can be occupied by ouabain without an impairment of the homeostasis. That portion of the ATPase which is not required for the maintenance of the homeostasis is believed to mediate the inotropic response upon occupation by cardiac glycosides. This may explain the observation that a given concentration of cardiac glycosides may act positive inotropic at low frequencies of contraction but toxic at higher beat frequencies.