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- Title
Effects of Anticancer Chemotherapeutic Drugs on the Acetylcholine Receptor-Operated Potassium Current in Guinea Pig Atrial Myocytes.
- Authors
Hara, Yukio; Kizaki, Keiichiro; Temma, Kyosuke; Chugun, Akihito; Kondo, Hiroshi
- Abstract
The effects of 7 anticancer chemotherapeutic drugs on the muscarinic acetylcholine receptor-operated potassium current (IK.ACh) in guinea pig atrial myocytes were investigated using the whole cell patch clamp technique. Doxorubicin, pirarubicin, and mitoxantrone inhibited the carbachol-induced IK.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 IK.ACh were 7.7μM, 3.7μM, and 9.1μM, respectively. Pirarubicin inhibited the adenosine-induced and the GTPγS-induced IK.ACh in a concentration-dependent manner (IC50=6.0 and 5.1μM, respectively). Doxorubicin and mitoxantrone up to 100μM did not have an influence on the adenosine-induced IK.ACh. Doxorubicin did not affect the GTPγS-induced IK.ACh. Mitoxantrone 100μM inhibited the current only by 25%. For concentrations up to 100μM, 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 IK.ACh. Doxorubicin and chemically related compounds possess anticholinergic effects mediated via an inhibitory action on IK.ACh by different underlying molecular mechanisms. Doxorubicin and mitoxantrone may inhibit IK.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.
- Subjects
ANTHRACYCLINES; CHOLINERGIC mechanisms; CHOLINERGIC receptors; MUSCARINIC receptors; FLUOROPYRIMIDINES; URACIL antagonists
- Publication
Basic & Clinical Pharmacology & Toxicology, 2004, Vol 95, Issue 5, p234
- ISSN
1742-7835
- Publication type
Article
- DOI
10.1111/j.1742-7843.2004.pto950506.x