Significance of sodium pump isoforms in digitalis therapy

Despite the long history of use of cardiac glycosides, questions persist relating to the very narrow range of therapeutic v toxic levels of the drug, and the factors, including hypokalemia, that predispose a patient to cardiac glycoside toxicity. The therapeutic receptor for cardiac glycosides is believed to be the alpha subunit of sodium pump, Na,K-ATPase. Three isoforms of this subunit are expressed in the heart, and the levels of cardiac sodium pump expression are depressed in heart failure. Which human sodium pump isoform(s) binds cardiac glycosides in the therapeutic range (1-2 nM for digoxin) in the failing heart has not been determined. Hypokalemia can potentially influence cardiac glycoside sensitivity at multiple levels: (1) it directly increases the affinity of cardiac glycosides for sodium pumps by decreasing competition with K+, (2) it decreases cardiac sodium pump expression which can augment or amplify the effects of decreased pump expression and activity due to heart failure itself and cardiac glycoside inhibition; (3) it decreases the expression of skeletal muscle sodium pumps which will influence the relative tissue and plasma distributions of cardiac glycosides. Establishing the therapeutic v toxic targets of cardiac glycosides will enable investigators to design isoform specific inhibitors that would potentially be specific for the therapeutic receptors and independent of plasma potassium levels.