title: Late sodium current inhibition alone with ranolazine is sufficient to reduce ischemia- and cardiac glycoside-induced calcium overload and contractile dysfunction mediated by reverse-mode sodium/calcium exchange.
abstract: Excessive reverse-mode (RM) sodium/calcium exchanger 1.1 (NCX1.1) activity, resulting from intracellular sodium accumulation caused by reduced Na+/K+-ATPase activity, increased Na-H exchanger 1 activity. The induction of the voltage-gated sodium channel late current component (late INa), is a major pathway for intracellular calcium (Ca2+i) loading in cardiac ischemia-reperfusion (IR) injury and cardiac glycoside toxicity. Inhibition of late INa with the antianginal agent ranolazine is protective in models of IR injury and cardiac glycoside toxicity. However, whether inhibition of late INa alone is sufficient to provide maximal protection or additional inhibition of RM NCX1.1 provides further benefit remains to be determined conclusively. Therefore, the effects of ranolazine were compared with the INa inhibitor lidocaine in models of IR injury and ouabain toxicity, RM NCX1.1-mediated Ca2+ overload, and patch-clamp assays of RM NCX1.1 currents. Ranolazine and lidocaine (10 μM) similarly reduced Ca2+i overload and improved left ventricle work recovery in whole-heart models of IR injury or exposure to ouabain (80 μM). Ranolazine (10 μM), but not lidocaine (10 μM), reduced RM NCX1.1-mediated Ca2+i overload in ventricular myocytes. Furthermore, ranolazine inhibited RM NCX1.1 currents (IC50 1.7 μM), without affecting forward mode currents, revealing that ranolazine has novel RM NCX1.1 inhibitory actions. However, because lidocaine provides similar protection to ranolazine in whole-heart models but does not inhibit RM NCX1.1, we conclude that induction of late INa is upstream of RM NCX1.1 activity and selective inhibition of late INa alone is sufficient to reduce Ca2+i overload and contractile dysfunction in IR injury and cardiac glycoside toxicity.
authors.affiliation: Cardiovascular Research Centre, Department of Pharmacology, Alberta Diabetes Institute, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada, T6G 2E1.
authors.forename: Daniel
authors.initials: D
authors.lastname: Soliman
authors.forename: Lianguo
authors.initials: L
authors.lastname: Wang
authors.forename: Kevin S C
authors.initials: KS
authors.lastname: Hamming
authors.forename: Wei
authors.initials: W
authors.lastname: Yang
authors.forename: Mohammad
authors.initials: M
authors.lastname: Fatehi
authors.forename: Christian C
authors.initials: CC
authors.lastname: Carter
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Clanachan
authors.forename: Peter E
authors.initials: PE
authors.lastname: Light
mesh_terms: D000083:Acetanilides / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects; D002301:Cardiac Glycosides / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D055724:Electrophysiological Phenomena / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D066298:In Vitro Techniques; D007511:Ischemia / Q000378:metabolism*; D008012:Lidocaine / Q000494:pharmacology; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy / Q000503:physiopathology; D018408:Patch-Clamp Techniques; D010879:Piperazines / Q000494:pharmacology*; D000069458:Ranolazine; D051381:Rats; D017207:Rats, Sprague-Dawley; D026941:Sodium Channel Blockers / Q000494:pharmacology*; D019831:Sodium-Calcium Exchanger / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D018487:Ventricular Dysfunction, Left / Q000188:drug therapy / Q000503:physiopathology
chemical_list: D000083:Acetanilides; D002301:Cardiac Glycosides; D004791:Enzyme Inhibitors; D010879:Piperazines; D026941:Sodium Channel Blockers; D019831:Sodium-Calcium Exchanger; C110374:sodium-calcium exchanger 1; D008012:Lidocaine; D000069458:Ranolazine; D002118:Calcium