Cardiac glycosides cause a reduction in sodium efflux from myocytes that leads to Na+ and Ca2+ overload, which has detrimental effects on mechanical function, energy metabolism, and electrical activity. Hoyer et al. hypothesized that inhibition of the sodium persistent inward current (late INa) would reduce ouabain's cellular Na+ and Ca2+ overloading. Ranolazine and tetrodotoxin, inhibitors of the late INa, significantly attenuated ouabain-stimulated increases in Nai2+ and INa, thus reducing the potential for cellular Na+ loading, metabolic and contractile dysfunction in cardiac myocytes. Ouabain also causes an increase in intracellular Ca2+; inhibition of Ca2+/calmodulin-dependent protein kinase II or inhibition of calcium overload with EGTA also reduces mechanical and electrical dysfunctions induced by ouabain. Taken together, these results suggest that late INa plays a role in glycoside-induced cardiac dysfunction and that direct or indirect inhibition of the late INa has the potential to be cardioprotective. Enhanced late INa causing Ca+2 overload, electrical, and mechanical dysfunction suggests a key pathophysiological role for late INa, inhibition of late INa in the diseased heart and during digitalis therapy may be of clinical relevance.
See article at J Pharmacol Exp Ther 2011, 337:513–523
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