Ouabain attenuates cardiotoxicity induced by other cardiac steroids

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 ) 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 (100 mg·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.

Endogenous ouabain regulates cell viability

“…6). Furthermore, in a study of the activity of CS on heart muscle contractility and rhythm, it was shown that different CS are even antagonistic to the effects of others (47). This diversity of action of the different CS may be of significance when considering the putative physiological roles of the different ECS.…”

Letter to the editor: “Why isn't clinical experience with ouabain more widely accepted?”

“…Thus this was "a surprise" in 1993. Nesher and colleagues (31) confirmed that ouabain and digoxin antagonize one another acutely but didn't address the mechanism (41). The mechanism for antagonizing the chronic effects of ouabain (26,27), not studied by Nesher, is apparently more complex (47).…”

“…was published online 4 days before Lewis and colleagues'(21); see our responses toLewis et al (2a,14)]; and 3) called the 1993 discovery of ouabaindigoxin antagonism (27) "a surprise," despite the 2010 report that ouabain antagonizes acute digoxin and bufalin cardiotoxicity(31).…”

Digoxin‐associated decrease in parathyroid hormone (PTH) concentrations in patients with atrial fibrillation

“…Although digoxin is a potent Na-K-ATPase inhibitor, similar to ouabain, there are some important differences between the two agents [8,13,14]. Although digoxin is a potent Na-K-ATPase inhibitor, similar to ouabain, there are some important differences between the two agents [8,13,14].…”