| Project/Area Number |
03404032
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| Research Category |
Grant-in-Aid for General Scientific Research (A)
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| Allocation Type | Single-year Grants |
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| Research Field |
Circulatory organs internal medicine
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| Research Institution | Tokyo Medical & Dental University, Medical Research Institute |
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Principal Investigator |
HIRAOKA Masayasu Tokyo Medical & Dental University, Medical Research Institute, Professor, 難治疾患研究所, 教授 (80014281)
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| Co-Investigator(Kenkyū-buntansha) |
HORIKAWA Saburo Tokyo Medical & Dental University, Medical Research Institute, Research Associat, 難治疾患研究所, 助手 (10127136)
HIRANO Yuji Tokyo Medical & Dental University, Medical Research Institute, Research Associat, 難治疾患研究所, 助手 (00181181)
SAWANOBORI Tohru Tokyo Medical & Dental University, Medical Research Institute, Assistant Profess, 難治疾患研究所, 助教授 (00014217)
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| Project Period (FY) |
1991 – 1993
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| Project Status |
Completed (Fiscal Year 1993)
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| Budget Amount *help |
¥12,700,000 (Direct Cost: ¥12,700,000)
Fiscal Year 1993: ¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 1992: ¥4,300,000 (Direct Cost: ¥4,300,000)
Fiscal Year 1991: ¥5,000,000 (Direct Cost: ¥5,000,000)
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| Keywords | class I antiarrhythmic drugs / Na^+ channel / State-dependent affinity / Blocking kinetics and modes / ventricular myocytes / patch-clamp technique / 使用依存性ブロック / イオン化型と非イオン化型薬物 / チャネル抑制の速度 / 荷電型と非荷電型薬物 / Na^+チャネル抑制の動態 / 心筋Na^+チャネル / 抗不整脈薬 / イオン化型と非イオン化型薬剤 / 活性化状態親和性 / 不活性化状態親和性 / パッチ・クラプ法 |
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| Research Abstract |
There have been considerable variation as to the subclassification of the class I antiarrhythmic drugs depending on the methodology to assess the drug actions, different preparations and individual reporters. As a possible reason for the above confusion, most of the reports dealt with the Na^+ channel block as assessed by measuring V_<max> of action potentials, an indirect index of the Na^+ channel availability rather than the current measurement. Therefore we tried to explore the modes of the Na^+ channel block by class I antiarrhythmic drugs directly assessed by the recordings of the cardiac Na^+ current using the patch-clamp technique and to obtain a new classification of the drugs based on the results. We used isolated ventricular myocytes from guinea-pig hearts by collagenase treatment. The Na^+ currents were recorded by the patch-clamp technique of whole-cell configuration, cell-attached and inside-out patch configurations, Disopyramide, I_a agent, produced used-dependent block of the Na^+ current with two exponential functions, fast and slow component. It was further shown by the experiments conducted under different external pH that the slow block process was caused by ionized form of the drug having affinity to bind the activated state of the Na^+ channel, while the fast process was produced by the non-ionized form to the activated state of the channel. The fast and slow block fractions consisted nearly equal degrees. Lidocaine, I_b agent, also caused two exponential block developments, while the major portion of the block development was brought by the fast fraction with small part by the slow component. The fast block was made by the non-ionized drug to bind the inactivated state of the channel and the slow block was caused by the ionized drug to the activated state of the channel. Mexyletine also caused two exponential block development as similar to lidocaine. The ionized mexiletine pr
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