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J. Biol. Chem., Vol. 280, Issue 1, 832-839, January 7, 2005

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Cardiotonic Steroids Differentially Affect Intracellular Na⁺ and [Na⁺]_i/[K⁺]_i-independent Signaling in C7-MDCK Cells^*

Olga A. Akimova, Alexei Y. Bagrov¶, Olga D. Lopina, Alexey V. Kamernitsky||, Johanne Tremblay, Pavel Hamet, and Sergei N. Orlov**

From the Centre de recherche, Centre hospitalier de l'Université de Montréal, Montreal, Quebec, H2W 1T7 Canada, the Faculty of Biology, Lomonosov Moscow State University, Moscow, 119899 Russia, ^¶Laboratory of Cardiovascular Science, NIA, National Institutes of Health, Baltimore, Maryland 21224, and the ^||Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Moscow, 119840 Russia

Recently, we reported that ouabain kills renal epithelial and vascular endothelial cells independently of elevation of the [Na⁺]_i/[K⁺]_i ratio. These observations raised the possibility of finding cardiotonic steroids (CTS) that inhibit the Na⁺,K⁺ pump without attenuating cell survival and vice versa. To test this hypothesis, we compared CTS action on Na⁺,K⁺ pump, [Na⁺]_i content, and survival of Madin-Darby canine kidney cells. At a concentration of 1 µM, ouabain and other tested cardenolides, as well as bufadienolides such as bufalin, cinobufagin, cinobufotalin, and telobufotoxin, led to 10-fold inhibition of the Na⁺,K⁺ pump, a 2-3-fold decrease in staining with dimethylthiazol-diphenyltetrazolium (MTT), and massive death indicated by detachment of 80% of cells and caspase-3 activation. In contrast, Na⁺,K⁺ pump inhibition and elevation of [Na⁺]_i seen in the presence of 3 µM marinobufagenin (MBG) and marinobufotoxin did not affect MTT staining and cell survival. Inhibition of the Na⁺,Rb⁺ pump in K⁺-free medium was not accompanied by a decline of MTT staining and cell detachment but increased sensitivity to CTS. In K⁺-free medium, half-maximal inhibition of ⁸⁶Rb influx was observed in the presence of 0.04 µM ouabain and 0.1 µM MBG, whereas half-maximal detachment and decline of MTT staining were detected at 0.03 and 0.004 µM of ouabain versus 10 and 3 µM of MBG, respectively. Both ouabain binding and ouabain-induced [Na⁺]_i,[K⁺]_i-independent signaling were suppressed in the presence of MBG. Thus, our results show that CTS exhibit distinctly different potency in Na⁺,K⁺ pump inhibition and triggering of [Na⁺]_i/[K⁺]_i-independent signaling, including cell death.

Received for publication, September 24, 2004 , and in revised form, October 12, 2004.

^* This work was supported by grants from the Canadian Institutes of Health Research (to P. H. and S. N. O.), the Heart and Stroke Foundation of Canada (to S. N. O., J. T., and P. H.), and the Kidney Foundation of Canada (to S. N. O.) and by a fellowship from the Palais de Congres de Montréal (to O. A. A.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^** To whom correspondence should be addressed: Centre de recherche, CHUM-Hôtel-Dieu, 3850 rue St-Urbain, Montreal, PQ H2W 1T7, Canada. Tel.: 514-890-8000 (ext. 12925); Fax: 514-412-7152; E-mail: sergei.n.orlov{at}umontreal.ca.

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