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Studies of influences of anticancer chemotherapeutic drugs on ligand-gated potassium current in heart muscle and their mechanism of actions

抗癌化疗药物对心肌配体门控钾电流的影响及其作用机制研究

基本信息

批准号：
09660327
负责人：
HARA Yukio
金额：
$ 2.05万
依托单位：
Kitasato 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

项目摘要

It has been reported that doxorubicin, an anthracycline anticancer chemotherapeutic agent, produces anticholinergic effects in heart. In the present study, the anticholinergic effects of 5 different anticancer chemotherapeutic agents were compared with the effect of doxorubicin by mean of cellular electrophysiological method. The acetylcholine-operated potassium channel (KAch) current induced by carbachol was measured by patch clamp method in isolated guinea-pig atrial myocytes. Only 2 drugs, doxorubicin and mitoxantrone, inhibited the KACh current in a concentration dependent manner. Both drugs reversed neither adenosine-induced KAch current nor adenosine-induced action potential shortening. Moreover, doxorubicin did not affect the intracellular GTPgammaS-activated KACh current. From these data, it is concludes that doxorubicin and mitoxantrone interact with muscarinic M2 receptor in myocardium to produce their anticholinergic effects.. Functional studies using isolated left atria and ileal muscles were conducted to confirm the interaction of doxorubicin with M2 and M3 receptors pharmacologically. In left atria and ilea, doxorubicin shifted the concentration-response curves for the negative inotropic effect and the contracting effect of carbachol to a same extent in a parallel manner. Thus, doxorubicin did not discriminate between M_2 and M_3 receptors. Atrial preparations from chronic doxorubicin-treated rats exhibited decreases in developed tension and the negative inotropic response to carbachol. However, there was rio quantitative change in GTP binding protein, which was measured by SDS-PAGE and western blotting method, in membrane preparation of ventricular muscle from chronic doxorubicin-treated rats. These results indicate that doxorubicin and chemically related anticancer chemotherapeutic agents exert anticholinergic effects. The site of anticholinergic action of the drugs is on muscarinic receptor level, similar to atropine.

据报道，阿霉素是一种蒽环类抗癌化疗药物，对心脏产生抗胆碱能作用。本研究通过细胞电生理方法比较了5种不同抗癌化疗药物的抗胆碱能作用与阿霉素的作用。采用膜片钳法测量离体豚鼠心房肌细胞中卡巴胆碱诱导的乙酰胆碱钾通道（KAch）电流。只有阿霉素和米托蒽醌两种药物以浓度依赖性方式抑制 KACh 电流。这两种药物既不能逆转腺苷诱导的 KAch 电流，也不能逆转腺苷诱导的动作电位缩短。此外，阿霉素不影响细胞内GTPgammaS激活的KACh电流。从这些数据可以得出结论，阿霉素和米托蒽醌与心肌中的毒蕈碱M2受体相互作用，产生抗胆碱能作用。使用分离的左心房和回肠肌肉进行功能研究，以在药理学上证实阿霉素与M2和M3受体的相互作用。在左心房和回肠中，阿霉素以平行方式将负性肌力作用和卡巴胆碱收缩作用的浓度-反应曲线移动到相同程度。因此，阿霉素不区分M_2和M_3受体。长期接受阿霉素治疗的大鼠的心房制剂表现出张力减弱和对卡巴胆碱的负性肌力反应。然而，在慢性阿霉素处理的大鼠心室肌膜制剂中，通过 SDS-PAGE 和蛋白质印迹法测量，GTP 结合蛋白出现了 rio 定量变化。这些结果表明阿霉素和化学相关的抗癌化疗剂发挥抗胆碱能作用。该药物的抗胆碱能作用位点位于毒蕈碱受体水平，与阿托品相似。