Alpha(1L)-, but not alpha(1H)-, adrenoceptor antagonist prevents allergic bronchoconstriction in guinea pigs in vivo

• Published in: European journal of pharmacology 2002-09, Vol.452 (1), p.97-104
• Main Authors: Nobata, Kouichi, Fujimura, Masaki, Ishiura, Yoshihisa, Hirose, Tatsuki, Furusyou, Shiho, Myou, Shigeharu, Kurashima, Kazuyoshi, Kasahara, Kazuo, Nakao, Shinji
• Format: Article
• Language: English
• Subjects: Adrenergic alpha-1 Receptor Antagonists; Adrenergic alpha-Antagonists - pharmacology; Animals; Blood Pressure - drug effects; Bronchoalveolar Lavage Fluid - chemistry; Bronchoconstriction - drug effects; Bronchoconstrictor Agents - pharmacology; Cresols - pharmacology; Guinea Pigs; Leukotriene C4 - metabolism; Male; Methacholine Chloride - pharmacology; Moxisylyte - pharmacology; Ovalbumin - immunology; Prazosin - pharmacology; Respiratory Hypersensitivity - immunology; Respiratory Hypersensitivity - physiopathology; Yohimbine - pharmacology
• ISSN: 0014-2999
• DOI: 10.1016/S0014-2999(02)02248-3

alpha-Adrenoceptors have been classified into alpha(1)- and alpha(2)-adrenoceptors. Recently, the alpha(1)-adrenoceptors were divided into two subtypes: alpha(1L) with low affinity and alpha(1H) with high affinity for prazosin. Little is known concerning the role of each subtype of alpha(1)-adrenoceptor in asthma. We investigated the effects of specific antagonists of alpha(1)- and alpha(2)-, alpha(1H)-, alpha(1L)-, and alpha(2)-adrenoceptors, namely moxisylyte, prazosin, 3-[N-[2-(4-hydroxy-2-isopropyl-5-methylphenoxy) ethyl]-N-methylaminomethyl]-4-methoxy-2, 5, 6-trimethylphenol hemifumarate (JTH-601), and yohimbine, respectively, on antigen-induced airway reactions in guinea pigs. Fifteen minutes after intravenous administration of moxisylyte (0.01, 0.1 or 1 mg/kg), prazosin (0.01, 0.1, 1 or 10 mg/kg), JTH-601 (1, 3, 6 or 10 mg/kg) or yohimbine (0.1 or 1 mg/kg), passively sensitized and artificially ventilated animals received an aerosolized antigen challenge. Bronchial responsiveness to inhaled methacholine was assessed as the dose of methacholine required to produce a 200% increase in the pressure at the airway opening (PC(200)) in non-sensitized animals. JTH-601 and moxisylyte, but not prazosin or yohimbine, dose dependently inhibited antigen-induced bronchoconstriction. None of the tested drugs altered PC(200). JTH-601 significantly reduced leukotriene C(4) levels in bronchoalveolar lavage fluid obtained 5 min after antigen challenge, but prazosin did not. These results indicate that prevention of antigen-induced bronchoconstriction by blockade of alpha-adrenoceptors is due to the inhibition of mediator release via alpha(1L)-adrenoceptor antagonism.