Modulation of the transducer function of Na(+),K(+)-ATPase: new mechanism of heart remodeling.

Endogenous digitalis-like factors were found in the mammalian and human blood. It was the starting point for the elucidation of the new non-pumping function of the Na(+),K(+)-ATPase. It was previously well known that Na(+),K(+)-ATPase is a pharmacological target receptor for cardiac glycosides (J.C. Skou. 1957. Biochim. Biophys. Acta, 23: 394-401). We have investigated the trophotropic effects of such agents as ouabain, epinephrine, norepinephrine, atenolol, and comenic acid using the organotypic tissue culture combined with the reconstruction of optical cross sections and confocal microscopy. It was shown that the growth zone of organotypic culture forms a multidimensional structure. Our results indicate that the cardiac glycoside ouabain applied in endogenous concentrations (10(-8), 10(-10) mol/L) can modulate transducer function of Na(+),K(+)-ATPase and control the cell growth and proliferation. It was also shown that Src-kinase is involved in "endogenous" ouabain activated intracellular pathways as a series unit. Epinephrine (10(-9)-10(-14) mol/L) and comenic acid (10(-6)-10(-10) mol/L) were demonstrated to modulate the growth of 10- to 12-day-old chicken embryo cardiac tissue explants in a dose-dependent manner. Epinephrine and comenic acid regulate growth and proliferation of the cardiac tissue via receptor-mediated modulation Na(+),K(+)-ATPase as a signal transducer. The trophotropic effects of the investigated agents specifically control the heart remodeling phenomenon.