EFFECTS OF CARDIAC DRUGS ON SODIUM-CALCIUM EXCHANGER

强心药对钠钙交换体的影响

• 批准号: 09670098
• 负责人: KIMURA Junko
• 金额: $ 2.05万
• 依托单位: FUKUSHIMA MEDICAL UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1997
• 资助国家: 日本
• 起止时间: 1997 至 1998
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09670098/
• 关键词: SODIUM-CALCIUM EXCHANGE CURRENT; WHOLE-CELL PATCH CLAMP; GUINEA PIG; INHIBITORS; TRANSPORTER; CALCIUM; SODIUM; ANTIARRHYTHMIC DRUG; DIABETES; TROGLITAZONE; 膜電流; リン酸化; Na-Ca交換電流; 心筋; 心臓作動薬; カルシウムイオン; ナトリウムイオン; トランスポータ

(1) KB-R7943 is a drug we first reported to inhibit Na-Ca exchange current (iNCX) with ICィイD250ィエD2 0.3 μM for outward iNCX and with 17μM for inward iNCX when one directional iNCX flows. However, under an experimental condition where bi-directional iNCX flows. The drug inhibits both outward and inward iNCX equipotently. This result can be explained by different conformation between the binding forms for external Na and Ca.(2) A new cardioprotective drug, JTV-519 inhibited Na-, Ca-, and inwardly rectifying K-currents in guinea pig cardiac ventricular cells. The block of Na current, was voltage- and use-dependent and was similar to quinidine rather than to lidocaine. ICィイD250ィエD2 for Na-current was 2 μM at -90 mV and 1.2 μM at -60 mV. The drug shortened the plateau of the action potential.(3) Butanedione monoxime (BDM) inhibited iNCX in guinea pig ventricular cells. ICィイD250ィエD2 value was 2.4 mM. A similar drug, pralidoxime also inhibited iNCX, indicating that dephosphorylation of the exchanger may be a reason. We are currently investigating mutated NCX for the mechanism of the drug action.(4) Class III antiarrhythmic drug, amiodarone inhibits iNCX. ICィイD250ィエD2 was 3 μM. Trypsin in the pipette solution diminished the inhibitory effect of amiodarone, indicating that the drug affects internal side of the exchanger.(5) Anti-diabetic drug, troglitazone inhibited L-type Ca current in guinea pig ventricular cells. The effect was voltage-dependent. ICィイD250ィエD2 values were 0.8 μM at a holding potential of -50 mV and larger than 10 μM at -80 mV.

(1)KB-R7943是我们首次报道的一种抑制Na-Ca交换电流的药物，当钠钙交换电流单向流动时，ICィイD250ィエD2 0.3μM抑制外向InCX，17μM抑制内向InCX。然而，在双向iNCX流动的实验条件下。该药物对外向和内向iNCX的抑制作用相同。这一结果可能是由于外源性钠钙结合形式不同所致。(2)新型心肌保护药JTV-519抑制豚鼠心肌细胞Na-、Ca-和内向整流钾电流。钠电流的阻断是电压和使用依赖性的，与奎尼丁相似，而不是利多卡因。钠电流的ICィイD250ィエD2在-90 mV时为2μM，在-60 mV时为1.2μM。(3)丁二酮肟(BDM)对豚鼠心室肌细胞iNCX有抑制作用。ICィイD250ィエD2值为2.4 mm。一种类似的药物，解磷定也抑制了iNCX，这表明交换器的去磷酸化可能是一个原因。我们目前正在研究突变的NCX的药物作用机制。(4)III类抗心律失常药物胺碘酮抑制iNCX。ICィイD250ィエD2为3μ。胰酶在吸管溶液中减弱了胺碘酮的抑制作用，表明药物影响到交换器的内侧。(5)抗糖尿病药物曲格列酮抑制豚鼠心室肌细胞的L型钙电流。这种效应是电压依赖的。ICィイD250ィエD2值在保持电位为-50 mV时为0.8μM，在-80 mV时大于10μM。

项目成果

Watano, T.: "Calcium-dependent inhibition of the soudium-calcium exchange current by KB-R7943" Canadian Journal of Cardiology. 14. 259-262 (1998)

Watano, T.：“KB-R7943 对钠-钙交换电流的钙依赖性抑制”加拿大心脏病学杂志。

Watano T.,Kimura J.: "Calcium-dependent inhibition of the sodium-calcium excharge current by KBR-7943" Canadian J.Cardiol.14(in press). (1998)

Watano T.，Kimura J.：“KBR-7943 对钠钙放电电流的钙依赖性抑制”Canadian J.Cardiol.14（印刷中）。

Kimura J.: "第11回国際女性技術者・科学者会議医療部門分科会記念医学論集"第11回国際女性技術者・科学者会議医療部門分科会. 162-165 (1999)

Kimura J.：“第 11 届国际女工程师和科学家会议医学部纪念医学论文集”第 11 届女工程师和科学家国际会议医学部 162-165 (1999)。

KATOH Yoko, HASHIMOTO Shigeatsu, KIMURA Junko, WATANABE Tsuyoshi: "Inhibitory action of troglitazone, an insulin-sensitizing agent, on the calcium current in cardiac ventricular cells of guinea-pig"Jpn. J. Pharmacol.. 82. 102-109 (2000)

加藤洋子、桥本重笃、木村顺子、渡边刚：“胰岛素增敏剂曲格列酮对豚鼠心室细胞钙电流的抑制作用”Jpn。

Watano T. & Kimura J.: "Calcium-dependent inhibition of the sodium-calcium exchange current by KB-R7943"Can.J.Cardiol.. 14. 259-262 (1998)

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