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 beta-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 muM), airway muscle was contracted with
acetylcholine or beta-ala
neurokinin A, followed by relaxation induced by cumulatively increasing concentrations of
isoproterenol (1 nM to 1 muM) in the absence or presence of the selective
GABA(A) agonist
muscimol (10-100 muM). In separate experiments, guinea pig tracheal rings were pretreated with the large conductance K(Ca) channel blocker
iberiotoxin (100 nM) after an EC(50) 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 beta-agonist-mediated relaxation of guinea pig and human airway smooth muscle, which may have important therapeutic implications for patients in severe
bronchospasm.