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This Article Full Text Full Text (PDF) All Versions of this Article: 295/6/L1040    most recent 90330.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Gallos, G. Articles by Emala, C. W. PubMed PubMed Citation Articles by Gallos, G. Articles by Emala, C. W.

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

Departments of ¹Anesthesiology and ²Surgery, College of Physicians and Surgeons of Columbia University, New York, New York

Submitted 2 June 2008 ; accepted in final form 10 September 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 GABA_A channels on airway smooth muscle cells. We questioned whether endogenous GABA_A channels on airway smooth muscle could augment β-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 GABA_A antagonist gabazine (100 µM), airway muscle was contracted with acetylcholine or β-ala neurokinin A, followed by relaxation induced by cumulatively increasing concentrations of isoproterenol (1 nM to 1 µM) in the absence or presence of the selective GABA_A agonist muscimol (10–100 µM). In separate experiments, guinea pig tracheal rings were pretreated with the large conductance K_Ca 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). GABA_A 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 K_Ca channel. Selective activation of endogenous GABA_A receptors significantly augments β-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