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1 Institute of Biochemistry and Endocrinology, University of Giessen, Frankfurter Str. 100, Giessen, D-35 392, Germany
2 Institute of Biochemistry and Endocrinology, Justus-Liebig-University Giessen, Giessen, Germany
* To whom correspondence should be addressed. E-mail: wilhelm.schoner{at}vetmed.uni-giessen.de.
Cardiotonic steroids (CTS), long used to treat heart failure, are endogenously produced in mammals. Amongst them are the hydrophilic cardenolide ouabain and the more hydrophobic cardenolide digoxin as well the bufadienolides marinobufagenin and telecinobufagin.
The physiological effects of endogenous ouabain on blood pressure and cardiac activity are consistent with the "Na+ lag" hypothesis. This assumes that in cardiac and arterial myocytes, a CTS-induced local increase of [Na+] due to the inhibition of Na+/K+-ATPase leads to an increase of [Ca2+]i via a backwards-running Na+/Ca2+-exchanger. This increase in [Ca2+]i then activates muscle contraction. This hypothesis may best explain short-term and inotropic actions of cardiotonic steroids. Yet, all data on the CTS-induced alteration of gene expression are consistent with another hypothesis based on the Na+/K+-ATPase "signalosome", which describes the interaction of cardiac glycosides with the sodium pump as machinery activating various signaling pathways via intramembrane and cytosolic protein-protein interactions. These pathways, which may be activated simultaneously or selectively, include the elevation of [Ca2+]i, activation of Src and the ERK1/2 kinase pathways, activation of PI3-kinase and protein kinase B (Akt), NF-
B and ROS.
Recent development indicates that new pharmaceuticals with antihypertensive and anticancer activities may be found amongst CTS and their derivatives: The antihypertensive Rostafuroxin suppresses Na+ resorbtion and the Src-EGFR-ERK pathway in kidney tubule cells. It may be the parent compound of a new principle of antihypertensive therapy. Bufalin and oleandrin or the cardenolide analog UNBS1450 block tumor cell proliferation and induce apoptosis at low concentrations in tumors with constitutive activation of NF-B.
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