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

阿霉素是一种蒽环类抗癌化疗药物，有研究表明其对心脏有抗胆碱能作用。本文用细胞电生理方法比较了5种不同抗癌化疗药物与阿霉素的抗胆碱能作用。用膜片钳技术观察了卡巴胆碱诱导的豚鼠心房肌细胞乙酰胆碱操纵钾通道（KAch）电流。只有2种药物，阿霉素和米托蒽醌，抑制KACh电流的浓度依赖性方式。两种药物既不逆转腺苷诱导的KAch电流，也不逆转腺苷诱导的动作电位缩短。此外，阿霉素不影响细胞内GTP γ S激活的KACh电流。以上结果表明，阿霉素和米托蒽醌与心肌M_2受体相互作用，产生抗胆碱能作用。使用离体左心房和回肠肌肉进行功能研究，以证实阿霉素与M2和M3受体的相互作用。在左心房和回肠中，阿霉素平行地使卡巴胆碱的负性肌力作用和收缩作用的浓度-反应曲线移动到相同的程度。因此，阿霉素不能区分M_2和M_3受体。慢性阿霉素治疗大鼠的心房制剂表现出发达的紧张和负性肌力反应卡巴胆碱减少。但用SDS-PAGE和Western blotting方法检测，慢性阿霉素处理的大鼠心室肌膜制备物中GTP结合蛋白的含量变化不大。这些结果表明，阿霉素和化学相关的抗癌化疗药物发挥抗胆碱能作用。这些药物的抗胆碱能作用部位在毒蕈碱受体水平，与阿托品相似。

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.