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

据报道，阿霉素是一种蒽环类抗癌化疗药物，在心脏中产生抗胆碱能作用。本研究采用细胞电生理方法，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。用膜片钳法测定了乙酰胆碱对豚鼠离体心房肌细胞钾通道电流的影响。只有阿霉素和米托蒽醌两种药物抑制KACh电流呈浓度依赖性。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。由此得出结论，阿霉素和米托蒽醌与心肌毒蕈碱M2受体相互作用，产生抗胆碱能作用。用离体左心房和回肠肌进行功能研究，从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，阿霉素使负性肌力作用的浓度-反应曲线和卡巴卡醇收缩作用的浓度-反应曲线平行移动相同程度。因此，阿霉素对M_2和M_3受体没有区别。慢性阿霉素治疗的大鼠心房制剂显示出发达的张力和负性肌力反应减少。而在慢性阿霉素处理大鼠心室肌膜制备过程中，采用SDS-PAGE和western blotting法测定GTP结合蛋白的定量变化为里约热内卢。这些结果表明，阿霉素和化学相关的抗癌化疗药物具有抗胆碱能作用。抗胆碱能作用部位与阿托品相似，在毒蕈碱受体水平。

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.