title: Involvement of Ca2+Signaling in the Synergistic Effects between Muscarinic Receptor Antagonists and β₂-Adrenoceptor Agonists in Airway Smooth Muscle.
abstract: Long-acting muscarinic antagonists (LAMAs) and short-acting β₂-adrenoceptor agonists (SABAs) play important roles in remedy for COPD. To propel a translational research for development of bronchodilator therapy, synergistic effects between SABAs with LAMAs were examined focused on Ca2+signaling using simultaneous records of isometric tension and F340/F380 in fura-2-loaded tracheal smooth muscle. Glycopyrronium (3 nM), a LAMA, modestly reduced methacholine (1 μM)-induced contraction. When procaterol, salbutamol and SABAs were applied in the presence of glycopyrronium, relaxant effects of these SABAs are markedly enhanced, and percent inhibition of tension was much greater than the sum of those for each agent and those expected from the BI theory. In contrast, percent inhibition of F340/F380 was not greater than those values. Bisindolylmaleimide, an inhibitor of protein kinase C (PKC), significantly increased the relaxant effect of LAMA without reducing F340/F380. Iberiotoxin, an inhibitor of large-conductance Ca2+-activated K⁺ (KCa) channels, significantly suppressed the effects of these combined agents with reducing F340/F380. In conclusion, combination of SABAs with LAMAs synergistically enhances inhibition of muscarinic contraction via decreasing both Ca2+sensitization mediated by PKC and Ca2+dynamics mediated by KCachannels. PKC and KCachannels may be molecular targets for cross talk between β₂-adrenoceptors and muscarinic receptors.
authors.affiliation: Division of Respiratory Medicine, Department of Internal Medicine, Shiga University of Medical Science, Seta, Tsukinowa-cho, Otsu, Shiga 520-2192, Japan. fukuken@belle.shiga-med.ac.jp.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Fukunaga
authors.affiliation: Department of Respiratory Medicine and Allergology, Kindai University Faculty of Medicine, 377-2 Ohnohigashi, Osakasayama, Osaka 589-8511, Japan. hkume@med.kindai.ac.jp.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Kume
authors.affiliation: Division of Respiratory Medicine, Department of Internal Medicine, Shiga University of Medical Science, Seta, Tsukinowa-cho, Otsu, Shiga 520-2192, Japan. oguma@belle.shiga-med.ac.jp.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Oguma
authors.affiliation: Division of Respiratory Medicine, Department of Internal Medicine, Shiga University of Medical Science, Seta, Tsukinowa-cho, Otsu, Shiga 520-2192, Japan. nitori@belle.shiga-med.ac.jp.
authors.forename: Wataru
authors.initials: W
authors.lastname: Shigemori
authors.affiliation: Department of Respiratory Medicine and Allergology, Kindai University Faculty of Medicine, 377-2 Ohnohigashi, Osakasayama, Osaka 589-8511, Japan. tohda@med.kindai.ac.jp.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Tohda
authors.affiliation: Division of Respiratory Medicine, Department of Internal Medicine, Shiga University of Medical Science, Seta, Tsukinowa-cho, Otsu, Shiga 520-2192, Japan. eogawa@belle.shiga-med.ac.jp.
authors.forename: Emiko
authors.initials: E
authors.lastname: Ogawa
authors.affiliation: Division of Respiratory Medicine, Department of Internal Medicine, Shiga University of Medical Science, Seta, Tsukinowa-cho, Otsu, Shiga 520-2192, Japan. nakano@belle.shiga-med.ac.jp.
authors.forename: Yasutaka
authors.initials: Y
authors.lastname: Nakano
keywords: COPD; Ca2+ dynamics; Ca2+ sensitization; cross talk; large-conductance Ca2+-activated K+ channel; procaterol; protein kinase C; tiotropium; tracheal smooth muscle