Pharmacological and Biochemical Studies on the Digitalis Receptor: A Two-Site Hypothesis for Positive Inotropic Action

Publisher Summary This chapter discusses two-site hypothesis for positive inotropic action. The mechanism of the positive inotropic effect of digitalis glycosides has not been fully elucidated. A casual relationship may exist between the binding to and consequent inhibition of Na, K-ATPase (the sodium pump) by digitalis and an increased myocardial contractile force, and/or the mechanism may have something to do with an increase in a sarcolemmal calcium pool without inhibition of the enzyme. The chapter reports that two distinct positive inotropic sites for ouabain exist in rat ventricular strips but not in atria. The higher-affinity site correlates with [3H]ouabain binding to intact rat ventricular myocytes and cardiac sarcolemma, but not with inhibition of Na, K-ATPase activity. Although a majority of studies of [3H]ouabain binding to various membrane preparations and purified Na, K-ATPase reveal a single Class of ouabain binding sites, several workers have recently obtained results, which are consistent with the existence of two populations of ouabain binding sites.