title: Characterization of mexiletine as an antagonist of beta-adrenoceptor in Chinese hamster ovary cells expressing cloned human beta-adrenoceptors.
abstract: We characterized the beta-adrenoceptor-blocking property of mexiletine, a class Ib antiarrhythmic drug, on Chinese hamster ovary (CHO) cells stably expressing cloned human beta1-, beta2-, and beta3-adrenoceptors. In radioligand binding experiments, mexiletine (10 microM-1 mM) concentration-dependently displaced the specific binding of [125I]cyanopindolol to human beta1- and beta2-adrenoceptors in the membrane fraction of the cells. High concentration (100 microM-1 mM) of mexiletine partially displaced the specific binding of [125I]cyanopindolol to human beta3-adrenoceptor. On the other hand, high concentration (300 microM and 1 mM) of lidocaine, another class Ib antiarrhythmic drug, partially displaced the specific binding of [125I]cyanopindolol to human beta1-adrenoceptor, whereas it did not affect the specific binding of [125I]cyanopindolol to human beta2- and beta3-adrenoceptors. Mexiletine (5, 50, and 500 microM) reduces basal adenosine 3',5'-cyclic monophosphate (cAMP) level and isoprenaline-induced cAMP accumulation on CHO cells stably expressing cloned human beta1- and beta2-adrenoceptors. Lidocaine (10 and 100 microM and 1 mM) tend to reduce basal cAMP level on CHO cells stably expressing cloned human beta1-adrenoceptors, whereas the drug did not reduce the isoprenaline-induced cAMP accumulation on CHO cells stably expressing cloned human beta1-, beta2-, and beta3-adrenoceptors. Mexiletine and lidocaine have no effect on forskolin (0.1, 1, and 3 microM)-induced cAMP accumulation. These results demonstrate that mexiletine blocks the binding of agonists to beta1- and beta2-adrenoceptors, and thereby attenuates the agonist-induced cAMP accumulation, and that the action of mexiletine as an antagonist of beta1- and beta2-adrenoceptors is independent of its antiarrhythmic property.
authors.affiliation: Department of Molecular Pharmacology, Kitasato University School of Pharmaceutical Sciences, 9-1 Shirokane 5-chome, Minato-ku, Tokyo 108-8641, Japan. sakamotok@pharm.kitasato-u.ac.jp
authors.forename: Kenji
authors.initials: K
authors.lastname: Sakamoto
authors.forename: Yuiko
authors.initials: Y
authors.lastname: Karikomi
authors.forename: Yuko
authors.initials: Y
authors.lastname: Kubota
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Nakahara
authors.forename: Kunio
authors.initials: K
authors.lastname: Ishii
mesh_terms: D058665:Adrenergic beta-1 Receptor Agonists; D058666:Adrenergic beta-2 Receptor Agonists; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D001667:Binding, Competitive; D016466:CHO Cells; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D005576:Colforsin / Q000494:pharmacology; D006224:Cricetinae; D000242:Cyclic AMP / Q000378:metabolism; D004347:Drug Interactions; D005260:Female; D006801:Humans; D007457:Iodine Radioisotopes; D007545:Isoproterenol / Q000494:pharmacology; D007700:Kinetics; D008012:Lidocaine / Q000494:pharmacology; D008801:Mexiletine / Q000494:pharmacology*; D010869:Pindolol / Q000031:analogs & derivatives* / Q000494:pharmacology; D018342:Receptors, Adrenergic, beta-1 / Q000235:genetics; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics; D014162:Transfection
chemical_list: D058665:Adrenergic beta-1 Receptor Agonists; D058666:Adrenergic beta-2 Receptor Agonists; D000319:Adrenergic beta-Antagonists; D000889:Anti-Arrhythmia Agents; D007457:Iodine Radioisotopes; D018342:Receptors, Adrenergic, beta-1; D018343:Receptors, Adrenergic, beta-2; D005576:Colforsin; D008801:Mexiletine; C047975:cyanopindolol; D008012:Lidocaine; D010869:Pindolol; D000242:Cyclic AMP; D007545:Isoproterenol