Physiological Modulations of Cardiac K^+ Currents by Ca^<2+> and their Roles for Arrhythmogenesis

Ca^2 对心脏 K^ 电流的生理调节及其在心律失常发生中的作用

• 批准号: 01480245
• 负责人: HIRAOKA Masayasu
• 金额: $ 4.54万
• 依托单位: Medical Research Institution, Tokyo Medical and Dental University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (B)
• 财政年份: 1989
• 资助国家: 日本
• 起止时间: 1989 至 1990
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-01480245/
• 关键词: Single heart cells; Patch-clamp technique; Whole-cell current recordings; Transient outward current; Delayed outward K^+ current; Ca^<2+>-influx; Increased internal Ca^<2+>; Ca^<2+>放出; 遅延外向きK^+電流; Co^<2+>; Ca^<2+>電流; 遅延整流K^+電流; 活動電位再分極相

In this research project, we studied two types of K+ currents in isolated vetricular myocytes from guinea-pig and rabbit hearts using the patch-clamp technique of the whole-cell configurations. The one type was the transient outward current (I_<to>) recorded from rabbit myocytes and the other was the delayed outward K^+ current (I_k) from guinea-pig myocytes. I_<to> was activated by step depolarizations positive to -20 mV I_<to> was found to be composed of two components, the Ca^<2+>-insensitive and Ca^<2+>-sensitive components. The Ca^<2+>-insensitive I_<to> was easily blocked by 4-aminopyridine and the Ca^<2+>-sensitive one was inhibited by caffeine. The latter component was also abolished by removing extracellular Ca^<2+> or application of Ca^<2+> blocking agents. It was inhibited by application of ryanidine. All of these results suggest that the Ca^<2+>-sensitive I_<to> was activated by Ca^<2+>-influx via the Ca^<2+> channel and/or increased internal Ca^<2+> through the Ca^<2+> rel … More ease from SR. The Ca^<2+>-sensitive I_<to> was increased during rapid stimulation and, therefore, it contributed the formation of the notch on action potential repolarization and its shortening during tachycardia.I_K was activated by depolarization positive to -50 mV and it contributed to the final repolarization phase. From the kinetic analysis of the tail current, I_k was separated by two components with a rapid and slow activation. The fast activating I_k was sensitive to Ca^<2+>-influx. Therefore, the inhibition of the Ca^<2+>-influx either by Ca^<2+> free solution or application of the Ca^<2+> antagonists produced a paradoxical prolongation of action potential duration, which was attributed to suppression of the fast activating I_k. The behaviors of I_k and action potential repolarizations were well simulated by the modulation of I_k by changes in internal Ca^<2+>. Co^<2+> was often used as a blocker of the Ca^<2+> channel but it also inhibited I_k at comparable concentrations. The mechanisms of the I_k block by Co^<2+> were shown to be screening the negative surface charges, decreasing the functional channel and additional voltage-dependent process. Therefore, Co^<2+> blocked I_k by multiple mechanisms. Less

在本研究项目中，我们使用全细胞结构膜片钳技术研究了豚鼠和兔离体心室肌细胞中两种类型的K+电流。一种是兔肌细胞瞬时外向电流（I_< ~ >），另一种是豚鼠肌细胞延迟外向K^+电流（I_k）。I_< ~ >由Ca^<2+>-不敏感组分和Ca^<2+>-敏感组分组成。Ca^<2+>-不敏感的I_<对>容易被4-氨基吡啶阻断，而Ca^<2+>-敏感的I_<被咖啡因抑制。后一种成分也可以通过去除细胞外Ca^<2+>或应用Ca^<2+>阻断剂来消除。苯胺对其有抑制作用。这些结果表明，Ca <2+>敏感I_<to>是通过Ca <2+>通道内流的Ca <2+>激活的，或者是通过Ca <2+>通道内流的Ca <2+>增加的。Ca <2+>敏感I_<to>在快速刺激时增加，从而促进了心动过速动作电位复极缺口的形成和缩短。I_K在-50 mV的正极下被激活，并参与了最终的复极化阶段。从尾电流的动力学分析来看，I_k被快速和缓慢激活的两个组分分离。快速激活I_k对Ca^<2+>-内流敏感。因此，Ca^<2+>游离溶液或Ca^<2+>拮抗剂对Ca^<2+>内流的抑制产生了动作电位持续时间的矛盾延长，这归因于抑制快速激活的I_k。通过改变内部Ca^<2+>对I_k的调制，可以很好地模拟I_k和动作电位的重极化行为。Co^<2+>常被用作Ca^<2+>通道的阻滞剂，但它也在相当浓度下抑制I_k。Co^<2+>阻滞I_k的机制被证明是屏蔽负表面电荷，减少功能通道和附加的电压依赖过程。因此，Co^<2+>通过多种机制阻塞I_k。少

项目成果

Hiraoka,M.and S.Kawano: "Beat-dependent increase in the caffeine-sensitive transient outward current in rabbit ventricuar myocytes." J.Mol.Cell.Cardiol.201(Supp1). S40 (1988)

Hiraoka，M. 和 S.Kawano：“兔心室肌细胞中咖啡因敏感的瞬时外向电流的节拍依赖性增加。”

平岡 昌和: "カリウムチャネルー研究の現状と臨床応用への展望" Therap.Res.11. 3497-3510 (1990)

Masakazu Hiraoka：“钾通道研究现状及临床应用前景”Therap.Res.11（1990）。

平岡 昌和: "心筋のカリウムチャネル" 心臓. (1991)

Masakazu Hiraoka：“心肌中的钾通道”Cardiac (1991)。

Hirano, Y., T. Sawanobori, M. Hiraoka and S. Abe :"Extracellular ATP-induced Ca^<2+> transients in mammalian atrial myocytes." Jpn. J. Physiol.40 (Suppl.). S268 (1990)

Hirano, Y.、T. Sawanobori、M. Hiraoka 和 S. Abe：“哺乳动物心房肌细胞中细胞外 ATP 诱导的 Ca^2 瞬变”。

Fan,Z.and M.Hiraoka: "Depression of the delayed outward K^+ current by Co^<2+> in guineaーpig ventricular myocytes." Am.J.Physiol.(Cell Physiol.). (1991)

Fan, Z. 和 M. Hiraoka：“Co^<2+> 对豚鼠心室肌​​细胞延迟外向 K^+ 电流的抑制。”(Am.J.Physiol.) (1991)。