Activation of endogenous GABA_A channels on airway smooth muscle potentiates isoproterenol-mediated relaxation

Abstract

Emala CW. Activation of endogenous GABAA channels on airway smooth muscle potentiates isoproterenol-mediated relaxation. Am J Physiol Lung Cell Mol Physiol 295: L1040 -L1047, 2008. First published September 12, 2008 doi:10.1152/ajplung.90330.2008.-Reactive airway disease predisposes patients to episodes of acute smooth muscle mediated bronchoconstriction. We have for the first time recently demonstrated the expression and function of endogenous ionotropic GABAA channels on airway smooth muscle cells. We questioned whether endogenous GABAA channels on airway smooth muscle could augment ␤-agonist-mediated relaxation. Guinea pig tracheal rings or human bronchial airway smooth muscles were equilibrated in organ baths with continuous digital tension recordings. After pretreatment with or without the selective GABAA antagonist gabazine (100 M), airway muscle was contracted with acetylcholine or ␤-ala neurokinin A, followed by relaxation induced by cumulatively increasing concentrations of isoproterenol (1 nM to 1 M) in the absence or presence of the selective GABAA agonist muscimol (10 -100 M). In separate experiments, guinea pig tracheal rings were pretreated with the large conductance KCa channel blocker iberiotoxin (100 nM) after an EC50 contraction with acetylcholine but before cumulatively increasing concentrations of isoproterenol (1 nM to 1 uM) in the absence or presence of muscimol (100 uM). GABAA activation potentiated the relaxant effects of isoproterenol after an acetylcholine or tachykinin-induced contraction in guinea pig tracheal rings or an acetylcholine-induced contraction in human endobronchial smooth muscle. This muscimol-induced potentiation of relaxation was abolished by gabazine pretreatment but persisted after blockade of the maxi KCa channel. Selective activation of endogenous GABAA receptors significantly augments ␤-agonist-mediated relaxation of guinea pig and human airway smooth muscle, which may have important therapeutic implications for patients in severe bronchospasm. guinea pig; organ bath; gabazine; muscimol ASTHMA IS A CHRONIC inflammatory disease of the airways the prevalence of which both in the United States and throughout much of the world has taken on pandemic proportions (4). Standard treatment for asthma centers on pharmacological attenuation of hyperresponsiveness either by modulation of inflammatory mediators or by promoting airway smooth muscle (ASM) relaxation (e.g., ␤ 2 -adrenoceptor agonists). Although research over the past three decades has made great strides in elucidating many of the underlying mechanisms involved in this disease, few novel additions to the pharmacological armamentarium have occurred in the treatment of reactive airway disease.␤ 2 -Adrenoceptor agonists retain a prominent role in the clinical treatment of airway hyperresponsiveness, and the mechanisms by which ␤ 2 -adrenoceptor agonists relax ASM include both cAMP-dependent and cAMP-independent pathways. Additionally, regulation of ␤ 2 -adrenoceptor activity either through desensitization or downregu...

Effects of inhaled aminophylline on airway constriction and inflammation in ovalbumin-sensitized guinea pigs

“…Aminophylline concentration-dependently suppressed ACh-induced contraction in the present study, similar to that observed in previous reports (Karlsson & Persson, 1981;Gallos et al, 2008). However, this study shows that overdoselevels rather than clinical doses (!20 mg/mL in serum) are required to achieve a strong relaxing effect.…”

“…To obtain concentration-response curves, aminophylline (range, 2.5-147 mg/mL) or saline (as control) were added to the organ bath at intervals of 20 min. At the end of the experiments, isoproterenol (10 mM; Sigma, Tokyo, Japan) was added; the percent relaxation by aminophylline was then calculated using the relaxation by isoproterenol as 100% (Gallos et al, 2008).…”

Targeting the γ-Aminobutyric Acid A Receptor α4 Subunit in Airway Smooth Muscle to Alleviate Bronchoconstriction

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Selective targeting of the α5-subunit of GABAA receptors relaxes airway smooth muscle and inhibits cellular calcium handling

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