title: Modification of distinct ion channels differentially modulates Ca2+dynamics in primary cultured rat ventricular cardiomyocytes.
abstract: Primary cultured cardiomyocytes show spontaneous Ca2+oscillations (SCOs) which not only govern contractile events, but undergo derangements that promote arrhythmogenesis through Ca2+-dependent mechanism. We systematically examined influence on SCOs of an array of ion channel modifiers by recording intracellular Ca2+dynamics in rat ventricular cardiomyocytes using Ca2+specific fluorescence dye, Fluo-8/AM. Voltage-gated sodium channels (VGSCs) activation elongates SCO duration and reduces SCO frequency while inhibition of VGSCs decreases SCO frequency without affecting amplitude and duration. Inhibition of voltage-gated potassium channel increases SCO duration. Direct activation of L-type Ca2+channels (LTCCs) induces SCO bursts while suppressing LTCCs decreases SCO amplitude and slightly increases SCO frequency. Activation of ryanodine receptors (RyRs) increases SCO duration and decreases both SCO amplitude and frequency while inhibiting RyRs decreases SCO frequency without affecting amplitude and duration. The potencies of these ion channel modifiers on SCO responses are generally consistent with their affinities in respective targets demonstrating that modification of distinct targets produces different SCO profiles. We further demonstrate that clinically-used drugs that produce Long-QT syndrome including cisapride, dofetilide, sotalol, and quinidine all induce SCO bursts while verapamil has no effect. Therefore, occurrence of SCO bursts may have a translational value to predict cardiotoxicants causing Long-QT syndrome.
authors.affiliation: State Key Laboratory of Natural Medicines &Jiangsu Provincial Key laboratory for TCM Evaluation and Translational Development, China Pharmaceutical University, Nanjing, Jiangsu, 211198 China.
authors.forename: Xichun
authors.initials: X
authors.lastname: Li
authors.affiliation: State Key Laboratory of Natural Medicines &Jiangsu Provincial Key laboratory for TCM Evaluation and Translational Development, China Pharmaceutical University, Nanjing, Jiangsu, 211198 China.
authors.forename: Liping
authors.initials: L
authors.lastname: Shen
authors.affiliation: State Key Laboratory of Natural Medicines &Jiangsu Provincial Key laboratory for TCM Evaluation and Translational Development, China Pharmaceutical University, Nanjing, Jiangsu, 211198 China.
authors.forename: Fang
authors.initials: F
authors.lastname: Zhao
authors.affiliation: State Key Laboratory of Natural Medicines &Jiangsu Provincial Key laboratory for TCM Evaluation and Translational Development, China Pharmaceutical University, Nanjing, Jiangsu, 211198 China.
authors.forename: Xiaohan
authors.initials: X
authors.lastname: Zou
authors.affiliation: State Key Laboratory of Natural Medicines &Jiangsu Provincial Key laboratory for TCM Evaluation and Translational Development, China Pharmaceutical University, Nanjing, Jiangsu, 211198 China.
authors.forename: Yuwei
authors.initials: Y
authors.lastname: He
authors.affiliation: State Key Laboratory of Natural Medicines &Jiangsu Provincial Key laboratory for TCM Evaluation and Translational Development, China Pharmaceutical University, Nanjing, Jiangsu, 211198 China.
authors.forename: Fan
authors.initials: F
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Natural Medicines &Jiangsu Provincial Key laboratory for TCM Evaluation and Translational Development, China Pharmaceutical University, Nanjing, Jiangsu, 211198 China.
authors.forename: Chunlei
authors.initials: C
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Natural Medicines &Jiangsu Provincial Key laboratory for TCM Evaluation and Translational Development, China Pharmaceutical University, Nanjing, Jiangsu, 211198 China.
authors.forename: Boyang
authors.initials: B
authors.lastname: Yu
authors.affiliation: State Key Laboratory of Natural Medicines &Jiangsu Provincial Key laboratory for TCM Evaluation and Translational Development, China Pharmaceutical University, Nanjing, Jiangsu, 211198 China.
authors.forename: Zhengyu
authors.initials: Z
authors.lastname: Cao
mesh_terms: D000814:Aniline Compounds / Q000032:analysis; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling; D002478:Cells, Cultured; D007473:Ion Channels / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000502:physiology*; D051381:Rats; D013194:Staining and Labeling; D014966:Xanthenes / Q000032:analysis
chemical_list: D000814:Aniline Compounds; D007473:Ion Channels; D014966:Xanthenes; C561295:fluo-8 AM; D002118:Calcium