Modulation of Ouabain Binding in Beating Ventricular Myocardium from Guinea-Pigs: Effects of Lidocaine and Monensin

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Abstract
To further elucidate the interdependence between digitalis sensitivity and the cellular Na+ load, the influence of two Na+ load modifying drugs, monensin and lidocaine, on the concentration-dependence of ouabain binding and ouabain effects was studied in beating ventricular strips from guinea-pig heart. Monensin (3 x 10(-6)M), a Na+ ionophore known to elevate Na+ influx, enhanced 3H-ouabain binding (by approximately 40%) as well as the ouabain effect at non-toxic ouabain concentrations, and it shifted the threshold for toxicity towards threefold lower ouabain concentrations. Lidocaine (2 x 10(-4)M), a Na+ channel blocker, lowered ouabain binding by about one third, and it extended the ouabain concentration range tolerated without toxicity by a factor of three. In the concentrations used, neither compound exerted any direct effect on ouabain binding studied in isolated cardiac membranes. The binding data obtained in the muscle strips were well fitted by a mathematical model which quantifies the dependence of ouabain binding on the underlying (Na+ +K+)-ATPase activity. These findings provide evidence for an indirect drug-induced modulation of ouabain binding via the interference with the cellular Na+ load.