Digitalis and the Na+,K(+)-ATPase.
Recent clinical, physiological, biochemical, and molecular biology studies strongly suggest that digitalis glycosides function in a complex manner through differential binding to and inactivation of multiple distinct Na+,K(+)-ATPase isoforms that are differentially expressed and regulated throughout the cardiovascular system. The alpha 1 isoform predominates in the ventricular: myocardium, whereas the alpha 2 and alpha 3 isoforms may localize to the conducting system structures. The peripheral vasculature also potentially expresses three digitalis receptors, as do neurons in the central nervous system. It is likely that similar heterogeneity exists in the autonomic nervous system as well as in the cardiopulmonary baroreceptor structures. Therefore, differential regulation of these isoforms, by either genetic predisposition or hormones, could dissociate contractile from conduction function and play a role in determining the degree, if any, of therapeutic response to digitalis glycosides. Similarly, genetic polymorphism of the alpha subunits has been observed in humans and rats and may play an important functional role in the ion transport function in a strain of hypertensive rats. Genetic differences in the regulation or structure and function of each isoform could confer allele-specific functional and pharmacological features such as predisposition to digitalis toxicity. Alterations in the degree and type of Na+,K(+)-ATPase isoforms expressed during cardiac hypertrophy and cardiac development may mediate increases or decreases in cardiac sensitivity to digitalis glycosides. This unexpected complexity of the digitalis receptor raises new questions about the role of digitalis glycosides in the treatment of congestive heart failure.
Medford
R M
RM
Department of Medicine, Emory University School of Medicine, Atlanta, Georgia.
D000818:Animals; D004071:Digitalis Glycosides / Q000627:therapeutic use*; D004077:Digoxin / Q000627:therapeutic use; D015870:Gene Expression; D006333:Heart Failure / Q000188:drug therapy*; D006801:Humans; D000254:Sodium-Potassium-Exchanging ATPase / Q000187:drug effects / Q000502:physiology*
D004071:Digitalis Glycosides; D004077:Digoxin; D000254:Sodium-Potassium-Exchanging ATPase