Gleason NR, Gallos G, Zhang Y, Emala CW
The GABAA Agonist Muscimol Attenuates Induced Airway Constriction in Guinea Pigs In Vivo. [JOURNAL ARTICLE]
J Appl Physiol 2009 Feb 12.
GABAA channels are ubiquitously expressed on neuronal cells and act via an inward chloride current to hyperpolarize the cell membrane of mature neurons. Expression and function of GABAA channels on airway smooth muscle cells has been demonstrated in vitro. Airway smooth muscle cell membrane hyperpolarization contributes to relaxation. We hypothesized that muscimol, a selective GABAA agonist, could act upon endogenous GABAA channels expressed on airway smooth muscle to attenuate induced increases in airway pressures in anesthetized guinea pigs in vivo. In an effort to localize muscimol's effect to GABAA channels expressed on airway smooth muscle, we pretreated guinea pigs with a selective GABAA antagonist (gabazine) or eliminated lung neural control from central parasympathetic, sympathetic and non-adrenergic, non-cholinergic (NANC) nerves before muscimol. Pretreatment with intravenous muscimol alone attenuated i.v. histamine-, i.v. acetylcholine- or vagal nerve stimulated-increases in peak pulmonary inflation pressure. Pretreatment with the GABAA antagonist gabazine blocked muscimol's effect. Following the elimination of neural input to airway tone by central parasympathetic nerves, peripheral sympathetic nerves, and non-adrenergic, non-cholinergic nerves intravenous muscimol retained its ability to block i.v. acetylcholine-induced increases in peak pulmonary inflation pressures. These findings demonstrate that the GABAA agonist muscimol acting specifically via GABAA channel activation attenuates airway constriction independent of neural contributions. These findings suggest that therapeutics directed at the airway smooth muscle GABAA channel may be a novel therapy for airway constriction following airway irritation and possibly more broadly in diseases such as asthma and COPD. Key words: acetylcholine, histamine, bronchospasm, gabazine.
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