| Budget Amount *help |
¥3,200,000 (Direct Cost: ¥3,200,000)
Fiscal Year 1998: ¥1,600,000 (Direct Cost: ¥1,600,000)
Fiscal Year 1997: ¥1,600,000 (Direct Cost: ¥1,600,000)
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| Research Abstract |
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.
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