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

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.