Ouabain attenuates cardiotoxicity induced by other cardiac steroids

M. Nesher, U. Shpolansky, N. Viola, M. Dvela, N. Buzaglo, H. Cohen Ben-Ami, H. Rosen, D. Lichtstein*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

35 Scopus citations

Abstract

Background and purpose: All cardiac steroids have a similar structure, bind to and inhibit the ubiquitous transmembrane protein Na +, K +-ATPase and increase the force of contraction of heart muscle. However, there are diverse biological responses to different cardiac steroids both at the cellular and at the molecular level. Moreover, we have recently shown that ouabain inhibits digoxin- and bufalin-induced changes in membrane traffic. The present study was designed to test the hypothesis that ouabain also has an inhibitory effect on cardiotoxicity induced by other cardiac steroids. Experimental approach: The hypothesis was tested in isolated heart muscle preparations and in an in vivo model of cardiotoxicity in guinea pigs. Key results: Ouabain at a low dose attenuated the toxicity induced by bufalin and digoxin in heart muscle preparations. In addition, ouabain at the low dose (91 ng·kg -1·h -1), but not at a higher dose (182 ng·kg -1·h -1), delayed the development of digoxin-induced (500g·kg -1·h -1) cardiotoxicity in anaesthetized guinea pigs, as manifested by delayed arrhythmia and terminal ventricular fibrillation, as well as a reduced heart rate. In addition, as observed with ouabain, the phosphoinositide 3-kinase inhibitor wortmannin (100g·kg -1·h -1) delayed the digoxin-induced arrhythmia in anaesthetized guinea pigs. Conclusions and implications: The present study demonstrates the inhibitory effect, probably through signal transduction pathways, of ouabain on digoxin- and bufalin-induced cardiotoxicity in guinea pigs. Further understanding of this phenomenon could be beneficial for increasing the therapeutic window for cardiac steroids in the treatment of chronic heart failure.

Original languageAmerican English
Pages (from-to)346-354
Number of pages9
JournalBritish Journal of Pharmacology
Volume160
Issue number2
DOIs
StatePublished - May 2010

Keywords

  • Arrhythmias
  • Bufalin
  • Cardiac glycosides
  • Digoxin
  • K -ATPase
  • Na
  • Wortmannin

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