The GABA_A agonist muscimol attenuates induced airway constriction in guinea pigs in vivo

Abstract

Gleason NR, Gallos G, Zhang Y, Emala CW. The GABAA agonist muscimol attenuates induced airway constriction in guinea pigs in vivo. J Appl Physiol 106: 1257-1263, 2009. First published February 12, 2009 doi:10.1152/japplphysiol.91314.2008.-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 on 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 nonadrenergic, noncholinergic (NANC) nerves before muscimol treatment. Pretreatment with intravenous muscimol alone attenuated intravenous histamine-, intravenous acetylcholine-, or vagal nerve-stimulated increases in peak pulmonary inflation pressure. Pretreatment with the GABAA antagonist gabazine blocked muscimol's effect. After the elimination of neural input to airway tone by central parasympathetic nerves, peripheral sympathetic nerves, and NANC nerves, intravenous muscimol retained its ability to block intravenous acetylcholineinduced increases in peak pulmonary inflation pressures. These findings demonstrate that the GABAA agonist muscimol acting specifically via GABAA channel activation attenuates airway constriction independently 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 chronic obstructive pulmonary disease. acetylcholine; histamine; vagal nerve stimulation; gabazine; guanethidine THERE HAS BEEN A GLOBAL INCREASE in the incidence of asthma in the last 20 years (4). Current asthma treatment focuses on avoiding triggers, reducing the incidence of exacerbations, and limiting airway inflammation and chronic remodeling. There have been few new developments in the pharmacological armamentarium against asthma over the last two decades and a paucity of new developments in the treatment of acute airway smooth muscle constriction, which is essential in the treatment of acute exacerbations.Recently, our laboratory identified ␥-aminobutyric acid type A (GABA A ) channels in human and animal airway smooth muscle (12). Activation of GABA A channels in mature central nervous system neurons results in an inward chloride flux resulting in hyperpolarization of the cell membrane (2). In airway smooth muscle, plasma membrane hyperpolarization favors relaxation (11). Although in vitro studies of...

Airway epithelium is a predominant source of endogenous airway GABA and contributes to relaxation of airway smooth muscle tone

“…Although we and others have characterized GABA effects on smooth muscle relaxation as well as GABA receptor expression in human airway (4,7,15,23), we are the first to investigate the source of GABA in the airway as illustrated in the present study. Three possible sources of GABA include airway epithelium, airway smooth muscle itself, and airway nerves.…”

Functional Expression of γ–Amino Butyric Acid Transporter 2 in Human and Guinea Pig Airway Epithelium and Smooth Muscle

“…GABA uptake can be decreased with cell membrane depolarization, similar to GAT in the CNS (25). These findings are of particular interest in the ASM, because depolarizing stimuli favor contraction of ASM, and we have previously shown that activation of GABA A channels can contribute to hyperpolarization and the subsequent relaxation of ASM (11,14,19). We further demonstrate that GATs in cultured human airway epithelial cells release 3 H-GABA under ionically favorable conditions, and that this release is significantly increased by cell membrane depolarization.…”

“…The emerging evidence of a role for both GABA A channels and GABA B receptors in ASM (8,10,14,19) and epithelium (7,9) led us to question the mechanism(s) by which synthesized GABA could be released from airway cells, and whether cells other than epithelial cells (i.e., smooth muscle) could be a source of GABA in the airway. Specifically, we questioned whether ASM also expresses GAD, and whether airway epithelium and smooth muscle cells functionally express the vesicular GAT (VGAT) or any of the four known GATs.…”

Targeting the restricted α-subunit repertoire of airway smooth muscle GABAA receptors augments airway smooth muscle relaxation

“…However, it has been a longstanding belief that any GABAergic contribution to airway tone was largely mediated by neurally mediated mechanisms (2,17,26). Our laboratory has demonstrated that airway smooth muscle GABA A receptor activation can both potentiate ␤-adrenoceptor agonist-mediated airway smooth muscle relaxation (in vitro) (7) as well as attenuate cholinergic-mediated airway resistance (in vivo) (8).…”