【摘 要】
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Primary cultured cardiomyocytes show synchronous Ca2+ oscillations (SCOs) which occur simultaneously with cardiomyocyte contraction and relaxation.In this study, we examined the influence of various i
【机 构】
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State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198,China
【出 处】
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2016(第二届)毒性测试替代方法与转化毒理学(国际)学术研讨会暨有害结局路径(AOP)与风险评估培训会议
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Primary cultured cardiomyocytes show synchronous Ca2+ oscillations (SCOs) which occur simultaneously with cardiomyocyte contraction and relaxation.In this study, we examined the influence of various ion channel modifies on the SCOs using Ca2+ specific fluorescence dye, FLuo-8/AM.Voltage-gated sodium channel (VGSC) agonists, veratridine reduces SCO frequency, induces multiple-peak SCOs and elongates the SCO duration.In contrast,TTX, the VGSC blocker, decreases the SCO frequency without affecting the SCO amplitude and peak duration.The universal voltage-gated potassium channel blocker, 4-amminopyridine increases the peak duration.E-4031, a specific Kv11.1 (hERG) channel blocker, induces multiple-peak SCOs therefore increases the peak duration with concomitant decrease in SCO frequency.Direct activation of L-type Ca2+ channels by BayK 8644 increases peak duration (FWHM).Blockade of L-type calcium channel by nifedipine decreases SCO amplitude and FWHM, increases SCO frequency.Ryanodine, an agonist of ryanodine receptor, increases FWHM and decreased both amplitude and frequency.FLA-365, a ryanodine receptor inhibitor, suppresses SCO frequency in a concentration-dependent manner without affecting SCO amplitude and FWHM.The IC50 or EC50 values of these positive drugs are general consistent with the affinities in their respective targets.These data demonstrate that distinct targets modification produce different SCO patterns.We further demonstrate that an array of clinic drugs (cisapride, dofetilide, sotalol, terfenadine and quinidine) that produce Long-QT syndrome all produce multiple-peak SCOs therefore increase the SCO duration (FWHM).On the contrast, verapamil although is a potent hERG inhibitor has no effect on the SCO duration.In addition, nifedipine, phenytoin and lamotrigine have no effect on the SCO duration although decrease the SCO frequeicy.Therefore, in addition to predict drug-induced tachycardia or bradycardia, prolonged SCO duration may serve as an index for drug-induced long-QT syndrome.
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