title: Ranolazine attenuates the enhanced reverse Na⁺-Ca²⁺ exchange current via inhibiting hypoxia-increased late sodium current in ventricular myocytes.
abstract: Ranolazine (RAN), a novel antianginal agent, inhibits the increased late sodium current (INa.L) under many pathological conditions. In this study, the whole-cell patch-clamp technique was used to explore the effects of RAN on INa.L and reverse Na(+)/Ca(2+) exchange current (INCX) in rabbit ventricular myocytes during hypoxia.Tetrodotoxin (TTX) at 2 μM or RAN at 9 μM decreased significantly INa.L and reverse INCX under normoxia and RAN had no further effects on both currents in the presence of TTX. RAN (3, 6, and 9 μM) attenuated hypoxia-increased INa.L and reverse INCX in a concentration-dependent manner. Hypoxia-increased INa.L and reverse INCX were inhibited by 2 μM TTX, whereas 9 μM RAN applied sequentially did not further decrease both currents. In another group, after both currents were decreased by 9 μM RAN, 2 μM TTX had no further effects in the presence of Ran. In monophasic action potential (MAP) recording, early after-depolarizations (EADs) were suppressed by RAN (9 μM) during hypoxia. In conclusion, RAN decreased reverse INCX by inhibiting INa.L in normoxia, concentration-dependently attenuated the increase of INa.L, which thereby decreased the reverse INCX, and obviously relieved EADs during hypoxia.
authors.affiliation: Cardio-Electrophysiological Research Laboratory, Medical College, Wuhan University of Science and Technology, China.
authors.forename: Xiao-Jing
authors.initials: XJ
authors.lastname: Wang
authors.forename: Lei-Lei
authors.initials: LL
authors.lastname: Wang
authors.forename: Chen
authors.initials: C
authors.lastname: Fu
authors.forename: Pei-Hua
authors.initials: PH
authors.lastname: Zhang
authors.forename: Ying
authors.initials: Y
authors.lastname: Wu
authors.forename: Ji-Hua
authors.initials: JH
authors.lastname: Ma
mesh_terms: D000083:Acetanilides / Q000494:pharmacology*; D000200:Action Potentials / Q000187:drug effects*; D000818:Animals; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006352:Heart Ventricles / Q000166:cytology*; D000860:Hypoxia / Q000378:metabolism* / Q000503:physiopathology*; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000502:physiology*; D018408:Patch-Clamp Techniques; D010879:Piperazines / Q000494:pharmacology*; D011817:Rabbits; D000069458:Ranolazine; D012964:Sodium / Q000378:metabolism*; D019831:Sodium-Calcium Exchanger / Q000378:metabolism*; D013779:Tetrodotoxin / Q000494:pharmacology
chemical_list: D000083:Acetanilides; D004791:Enzyme Inhibitors; D010879:Piperazines; D019831:Sodium-Calcium Exchanger; D013779:Tetrodotoxin; D012964:Sodium; D000069458:Ranolazine