title: Inhibitory effects of amlexanox on carbachol-induced contractions of rabbit ciliary muscle and guinea-pig taenia caecum.
abstract: Instillation of amlexanox, an anti-allergic drug, over a long period improves myopia in some allergy patients and in monkeys. The relaxing effect of amlexanox on persistent contraction of ciliary muscle may be involved in the improvement of myopia. In this study, the mechanism of the noncompetitive inhibition of carbachol-induced contractions by amlexanox (1-100 microM) was investigated in isolated smooth muscle preparations of the rabbit ciliary body and guinea-pig taenia caecum. In ciliary muscles, amlexanox (100 microM) inhibited both the phasic and tonic components of carbachol-induced contractions even in the presence of cyclopiazonic acid (10 microM) where the function of the sarcoplasmic reticulum was impaired, while diltiazem (3.2, 32 microM) did not. In taenia caecum, diltiazem (3.2 microM) slightly inhibited the phasic component and abolished the tonic component of carbachol-induced contractions. Amlexanox also abolished the tonic component, but it did not decrease the 45Ca2+ uptake into taenia caecum smooth muscle cells induced by carbachol. Amlexanox did not increase the cyclic adenosine monophosphate (cyclicAMP) content of ciliary muscles in the presence of 3-isobutyl-1-methylxanthine (10 microM), while forskolin (1 microM) did. Gel-shift assay showed that the inhibition of carbachol-induced contractions by amlexanox was accompanied by a decrease in phosphorylation of the 20-kDa myosin light chain in taenia caecum tissue preparations. Amlexanox had no effect on calmodulin activity, whereas it inhibited phosphorylation of the myosin light chain by purified myosin light-chain kinase from chicken gizzard. These results suggested that amlexanox may not affect either Ca2+ mobilization or calmodulin activity, although it inhibits myosin light-chain kinase, which may inhibit carbachol-induced contraction.
authors.affiliation: Department of Pharmacobiodynamics, Faculty of Pharmaceutical Sciences, Kanazawa University, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Watanabe
authors.forename: Y
authors.initials: Y
authors.lastname: Tominaga
authors.forename: K
authors.initials: K
authors.lastname: Mizutani
authors.forename: T
authors.initials: T
authors.lastname: Ogawa
authors.forename: H
authors.initials: H
authors.lastname: Tsunobuchi-Ushijima
authors.forename: Y
authors.initials: Y
authors.lastname: Gomi
mesh_terms: D000631:Aminopyridines / Q000494:pharmacology*; D000818:Animals; D018926:Anti-Allergic Agents / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002217:Carbachol / Q000494:pharmacology*; D002432:Cecum / Q000187:drug effects* / Q000502:physiology; D018679:Cholinergic Agonists / Q000494:pharmacology*; D002924:Ciliary Body / Q000187:drug effects* / Q000502:physiology; D000242:Cyclic AMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D009119:Muscle Contraction / Q000187:drug effects*; D009130:Muscle, Smooth / Q000502:physiology; D009216:Myopia / Q000188:drug therapy; D009219:Myosin-Light-Chain Kinase; D010766:Phosphorylation; D011817:Rabbits
chemical_list: D000631:Aminopyridines; D018926:Anti-Allergic Agents; D018679:Cholinergic Agonists; D002217:Carbachol; C045742:amlexanox; D000242:Cyclic AMP; D009219:Myosin-Light-Chain Kinase; D002118:Calcium