Effects of anticancer chemotherapeutic drugs on the acetylcholine receptor-operated potassium current in guinea pig atrial myocytes.
The effects of 7 anticancer chemotherapeutic drugs on the muscarinic acetylcholine receptor-operated potassium current (I(K.ACh)) in guinea pig atrial myocytes were investigated using the whole cell patch clamp technique. Doxorubicin, pirarubicin, and mitoxantrone inhibited the carbachol-induced I(K.ACh) in a concentration-dependent manner in atrial cells at a holding potential of -40 mV. IC50 values of doxorubicin, pirarubicin, and mitoxantrone for the carbachol-induced I(K.ACh) were 7.7 microM, 3.7 microM, and 9.1 microM, respectively. Pirarubicin inhibited the adenosine-induced and the GTPgammaS-induced I(K.ACh) in a concentration-dependent manner (IC50=6.0 and 5.1 microM, respectively). Doxorubicin and mitoxantrone up to 100 microM did not have an influence on the adenosine-induced I(K.ACh). Doxorubicin did not affect the GTPgammaS-induced I(K.ACh). Mitoxantrone 100 microM inhibited the current only by 25%. For concentrations up to 100 microM, anticancer drugs that have chemical structures entirely different from that of doxorubicin, i.e., 5-fluorouracil, 6-mercaptopurine, cyclophosphamide, and actinomycin D, did not have an influence on the carbachol-induced I(K.ACh). Doxorubicin and chemically related compounds possess anticholinergic effects mediated via an inhibitory action on I(K.ACh) by different underlying molecular mechanisms. Doxorubicin and mitoxantrone may inhibit I(K.ACh) by the blockade of muscarinic receptors, whereas pirarubicin may inhibit the current not only via blocking the muscarinic receptors but also by depressing the functions of the K+ channel itself and/or GTP-binding proteins.
Hara
Yukio
Y
Department of Veterinary Pharmacology, School of Veterinary Medicine and Animal Sciences, Kitasato University, Towada, Aomori 034-8628, Japan. hara@vmas.kitasato-u.ac.jp
Kizaki
Keiichiro
K
Temma
Kyosuke
K
Chugun
Akihito
A
Kondo
Hiroshi
H
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D006325:Heart Atria / Q000166:cytology; D008564:Membrane Potentials / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000378:metabolism*; D011976:Receptors, Muscarinic / Q000378:metabolism*
D000970:Antineoplastic Agents; D015221:Potassium Channels; D011976:Receptors, Muscarinic