title: Reducing the late sodium current improves cardiac function during sodium pump inhibition by ouabain.
abstract: Inhibition by cardiac glycosides of Na(+), K(+)-ATPase reduces sodium efflux from myocytes and may lead to Na(+) and Ca(2+) overload and detrimental effects on mechanical function, energy metabolism, and electrical activity. We hypothesized that inhibition of sodium persistent inward current (late I(Na)) would reduce ouabain's effect to cause cellular Na(+) loading and its detrimental metabolic (decrease of ATP) and functional (arrhythmias, contracture) effects. Therefore, we determined effects of ouabain on concentrations of intracellular sodium (Na(+)(i)) and high-energy phosphates using (23)Na and (31)P NMR, the amplitude of late I(Na) using the whole-cell patch-clamp technique, and contractility and electrical activity of guinea pig isolated hearts, papillary muscles, and ventricular myocytes in the absence and presence of inhibitors of late I(Na). Ouabain (1-1.3 μM) increased Na(+)(i) and late I(Na) of guinea pig isolated hearts and myocytes by 3.7- and 4.2-fold, respectively. The late I(Na) inhibitors ranolazine and tetrodotoxin significantly reduced ouabain-stimulated increases in Na(+)(i) and late I(Na). Reductions of ATP and phosphocreatine contents and increased diastolic tension in ouabain-treated hearts were also markedly attenuated by ranolazine. Furthermore, the ouabain-induced increase of late I(Na) was also attenuated by the Ca(2+)-calmodulin-dependent kinase I inhibitors KN-93 [N-[2-[[[3-(4-chlorophenyl)-2-propenyl]methylamino]methyl]phenyl]-N-(2-hydroxyethyl)-4-methoxybenzenesulphonamide] and autocamide-2 related inhibitory peptide, but not by KN-92 [2-[N-(4'-methoxybenzenesulfonyl)]amino-N-(4'-chlorophenyl)-2-propenyl-N-methylbenzylamine phosphate]. We conclude that ouabain-induced Na(+) and Ca(2+) overload is ameliorated by the inhibition of late I(Na).
authors.affiliation: Department of Biology, Gilead Sciences, Inc., Palo Alto, CA 94304, USA. kirsten.hoyer@gilead.com
authors.forename: Kirsten
authors.initials: K
authors.lastname: Hoyer
authors.forename: Yejia
authors.initials: Y
authors.lastname: Song
authors.forename: Desuo
authors.initials: D
authors.lastname: Wang
authors.forename: Dillon
authors.initials: D
authors.lastname: Phan
authors.forename: James
authors.initials: J
authors.lastname: Balschi
authors.forename: Joanne S
authors.initials: JS
authors.lastname: Ingwall
authors.forename: Luiz
authors.initials: L
authors.lastname: Belardinelli
authors.forename: John C
authors.initials: JC
authors.lastname: Shryock
mesh_terms: D000083:Acetanilides / Q000008:administration & dosage / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D055724:Electrophysiological Phenomena; D004734:Energy Metabolism / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006168:Guinea Pigs; D006321:Heart / Q000502:physiology*; D006334:Heart Function Tests; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000737:chemistry / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects; D010042:Ouabain / Q000494:pharmacology*; D010210:Papillary Muscles / Q000187:drug effects; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology; D000069458:Ranolazine; D012964:Sodium / Q000032:analysis / Q000378:metabolism; D026941:Sodium Channel Blockers / Q000008:administration & dosage / Q000494:pharmacology; D015222:Sodium Channels / Q000502:physiology*; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors*; D013779:Tetrodotoxin / Q000008:administration & dosage / Q000494:pharmacology
chemical_list: D000083:Acetanilides; D004791:Enzyme Inhibitors; D010879:Piperazines; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D013779:Tetrodotoxin; D010042:Ouabain; D000255:Adenosine Triphosphate; D012964:Sodium; D000069458:Ranolazine; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D000254:Sodium-Potassium-Exchanging ATPase