title: Protein kinase C and Ca(2+) -calmodulin-dependent protein kinase II mediate the enlarged reverse INCX induced by ouabain-increased late sodium current in rabbit ventricular myocytes.
abstract: What is the central question of this study? What are the effects of protein kinase C (PKC) and Ca(2+) -calmodulin-dependent protein kinase II (CaMKII) on late sodium current (INaL ), reverse Na(+) -Ca(2+) exchange current (reverse INCX ) or intracellular Ca(2+) levels changed by ouabain? What is the main finding and its importance? Ouabain, even at low concentrations (0.5-8.0 μm), can increase INaL and reverse INCX , and these effects may contribute to the effect of the glycoside to increase Ca(2+) transients and contractility. Both PKC and CaMKII activities may mediate or modulate these processes. It has been reported that the cardiac glycoside ouabain can increase the late sodium current (INaL ), as well as the diastolic intracellular calcium concentration and contractile shortening. Whether an increase of INaL participates in a pathway that can mediate the positive inotropic response to ouabain is unknown. We therefore determined the effects of ouabain on INaL , reverse Na(+) -Ca(2+) exchange current (reverse INCX ), intracellular Ca(2+) ([Ca(2+) ]i ) levels and contractile shortening in rabbit isolated ventricular myocytes. Ouabain (0.1-8 μm) markedly increased INaL and reverse INCX in a concentration-dependent manner, with significant effects at concentrations as low as 0.5 and 1 μm. These effects of ouabain were suppressed by the INaL inhibitors TTX and ranolazine, the protein kinase C inhibitor bisindolylmaleimide and the Ca(2+) -calmodulin-dependent protein kinase II inhibitor KN-93. The enhancement by 0.5 μm ouabain of ventricular myocyte contractility and intracellular Ca(2+) transients was suppressed by 2.0 μm TTX. We conclude that ouabain, even at low concentrations (0.5-8.0 μm), can increase INaL and reverse INCX , and these effects may contribute to the effect of the glycoside to increase Ca(2+) transients and contractility. Both protein kinase C and Ca(2+) -calmodulin-dependent protein kinase II activities may mediate or modulate these processes.
authors: Cardio-Electrophysiological Research Laboratory, Medical College of Wuhan University of Science and Technology, Wuhan, China.
authors: Ying
authors: Y
authors: Wu
authors: Leilei
authors: L
authors: Wang
authors: Jihua
authors: J
authors: Ma
authors: Yejia
authors: Y
authors: Song
authors: Peihua
authors: P
authors: Zhang
authors: Antao
authors: A
authors: Luo
authors: Chen
authors: C
authors: Fu
authors: Zhenzhen
authors: Z
authors: Cao
authors: Xiaojing
authors: X
authors: Wang
authors: John C
authors: JC
authors: Shryock
authors: Luiz
authors: L
authors: Belardinelli
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism*; D002316:Cardiotonic Agents / Q000008:administration & dosage; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D006352:Heart Ventricles / Q000166:cytology / Q000378:metabolism; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology*; D010042:Ouabain / Q000008:administration & dosage*; D011493:Protein Kinase C / Q000378:metabolism*; D011817:Rabbits; D012964:Sodium / Q000378:metabolism*
chemical_list: D002316:Cardiotonic Agents; D004791:Enzyme Inhibitors; D010042:Ouabain; D012964:Sodium; D011493:Protein Kinase C; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D002118:Calcium