title: Mexiletine inhibits pharmacological actions of salbutamol through blockade of beta2-adrenoceptors in bovine tracheal smooth muscle.
abstract: We examined the effects of mexiletine, a class Ib antiarrhythmic drug, on the changes in tension and adenosine 3',5'-cyclic monophosphate (cAMP) content induced by salbutamol and forskolin in bovine tracheal smooth muscle. Salbutamol (0.0001-1 microM) produced concentration-dependent relaxation in bovine tracheal smooth muscle contracted with methacholine (0.3 microM). Mexiletine (5-500 microM) caused the rightward shifts of concentration-response curves for the relaxant responses to salbutamol in a concentration-dependent manner. Mexiletine (5, 50 or 500 microM) did not change basal cAMP levels, whereas it concentration-dependently attenuated the salbutamol (0.1 microM)-induced cAMP accumulation. On the other hand, mexiletine (500 microM) did not change the concentration-response curves for the relaxant responses to forskolin (0.001-10 microM). Mexiletine slightly but significantly (P<0.05) increased forskolin (1 microM)-induced cAMP accumulation. In radioligand binding experiments, mexiletine concentration-dependently displaced the specific binding of [125I]cyanopindolol to beta-adrenoceptors on bovine tracheal smooth muscle membranes. By contrast, lidocaine, another class Ib antiarrhythmic drug, did not change the binding of [125I]cyanopindolol. These results demonstrate that mexiletine prevents the binding of beta2-adrenoceptor agonists to their receptors and thereby suppresses manifestation of subsequent pharmacological responses.
authors.affiliation: Department of Molecular Pharmacology, Kitasato University School of Pharmaceutical Sciences, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan. nakaharat@pharm.kitasato-u.ac.jp
authors.forename: T
authors.initials: T
authors.lastname: Nakahara
authors.forename: Y
authors.initials: Y
authors.lastname: Kubota
authors.forename: K
authors.initials: K
authors.lastname: Sakamato
authors.forename: H
authors.initials: H
authors.lastname: Moriuchi
authors.forename: M
authors.initials: M
authors.lastname: Yunoki
authors.forename: K
authors.initials: K
authors.lastname: Ishii
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000420:Albuterol / Q000037:antagonists & inhibitors*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001993:Bronchodilator Agents / Q000037:antagonists & inhibitors*; D002417:Cattle; D000242:Cyclic AMP / Q000378:metabolism; D008012:Lidocaine / Q000494:pharmacology*; D008801:Mexiletine / Q000494:pharmacology*; D009126:Muscle Relaxation / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects* / Q000378:metabolism; D014132:Trachea
chemical_list: D000319:Adrenergic beta-Antagonists; D000889:Anti-Arrhythmia Agents; D001993:Bronchodilator Agents; D008801:Mexiletine; D008012:Lidocaine; D000242:Cyclic AMP; D000420:Albuterol