Endogenous cardiotonic steroids: clinical perspectives

Abstract

Several endogenous digitalis-like cardiotonic steroids (CTS) have been identified in humans, including endogenous ouabain, a cardenolide, and marinobufagenin which belongs to a class of bufadienolides. The main function of CTS is maintenance of sodium homeostasis and regulation of natriuretic function. Endogenous cardiotonic steroids bind to the Na/K-ATPase and exhibit two kinds of effects, inhibition of transmembrane transport of monovalent cations, and induction of a complex cascade of cell signaling. In Dahl salt-sensitive rats with NaCl-induced hypertension, endogenous ouabain, acting as a neurohormone stimulates adrenocortical marinobufagenin, which raises blood pressure via inhibition of vascular Na/K-ATPase. In a subgroup of hypertensive subjects, which possess a polymorphism of alpha-adducin gene, elevated levels of endogenous ouabain activate renotubular Na/K-ATPase and induce renal sodium retention. Elevated levels of CTS also contribute to pathogenesis of congestive heart failure, preeclampsia, and diabetes mellitus. The approaches to pharmacological antagonism of the effects of CTS include blockade of CTS receptor site on the Na/K-ATPase, immunoneutralization, and interactions at the levels of Na/K-ATPase phosphorylation/dephosphorylation by protein kinases С and G.