Prejunctional GABA-B inhibition of cholinergic, neurally-mediated airway contractions in guinea-pigs

Chapman, Richard W.; Danko, Gisela; Rizzo, Charles A.; Egan, Robert W.; Mauser, Peter; Kreutner, William

doi:10.1016/0952-0600(91)90014-t

Cited by 39 publications

(35 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The GABAB receptor mediating the effect of GABA was not sensitive to the receptor agonist, 3-APA. Since it has been previously reported that contraction of tracheal strips by electrical stimulation was sensitive to both baclofen and 3-APA (Chapman et al, 1991), this discrepancy may suggest GABAB receptor heterogeneity, although further investigation is required. Superfusion of tracheal strips with TTX significantly increased OA-induced contractions, suggesting that a neurogenic inhibitory mechanism could be activated in response to challenge with the allergen.…”

Section: Discussionmentioning

confidence: 80%

“…Following our observation that GABAmimetic agents protect from allergic bronchospasm in guinea-pigs , the existence of both GABAA and GABAB receptors has been pharmacologically demonstrated in the mammalian respiratory tract (Tamaoki et al, 1987;Shirakawa et al, 1987;Belvisi et al, 1989;Ray et al, 1991;Chapman et al, 1991;1993). These receptors for GABA are responsible for the inhibition of tracheal bronchial smooth muscle contraction in vivo and in vitro, and for the reduced release of transmitters which stimulate the airway smooth muscles.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

GABA‐mediated inhibition of the anaphylactic response in the guinea‐pig trachea

Gentilini

Franchi‐Micheli

Mugnai

et al. 1995

British J Pharmacology

View full text Add to dashboard Cite

In sensitized guinea‐pigs, the effects of γ‐aminobutyric acid (GABA) and GABAmimetic drugs have been investigated on tracheal segments contracted by cumulative application of an allergen (ovoalbumin, OA) and on serosal mast cells. The same drugs have also been tested on activation of alveolar macrophages isolated from unsensitized guinea‐pigs. Superfusion with GABA (1–1000 μM) reduced the contraction intensity of tracheal strips. The effect of GABA (100 μM) was not affected by the carrier blockers, nipecotic acid and β‐alanine (300 μM each). It was mimicked by the GABAB agonist (−)−baclofen (100 μM) but not 3‐aminopropanephosphinic acid (100 μM, 3‐APA). The GABAA agonist, isoguvacine (100 μM) did not exert any effect. GABA (10 μM)‐induced inhibition of tracheal contractions was reduced by the GABAB antagonist, 2‐hydroxysaclofen (100 μM, 2‐HS), but not by the GABAA antagonist, bicuculline (30 μM). The reduction in contraction intensity induced by GABA (100 μM) was prevented by a 40 min preincubation of tracheal strips with capsaicin (10 μM), but not tetrodotoxin (TTX, 0.3 μM). The effect of GABA (1000 μM) was absent after preincubation with indomethacin (2.8 μM) but unmodified when nordihydroguaiaretic acid (NDGA, 3.3 μM) was used. Finally, removal of the epithelium prevented the GABA effect. Anaphylactic histamine release from serosal mast cells isolated from sensitized animals was not affected either by GABA (10–1000 μM) or the selective receptor agonists (−)−baclofen (0.1–1000 μM) and isoguvacine (10–1000 μM). The release of platelet‐activating factor (PAF) from alveolar macrophages stimulated by formyl‐Met‐Leu‐Phe (FMLP; 1 μM) was modified neither by GABA (100 μM) nor by (−)−baclofen (100 μM). In conclusion, these data show that GABA can inhibit allergic phenomena in the guinea‐pig airways through activation of GABAB receptors. An involvement of neuropeptidergic sensory structures is suggested but a role for epithelial cells and arachidonate metabolites is not definitely proved.

show abstract

Section: Discussionmentioning

confidence: 80%

Section: Introductionmentioning

confidence: 99%

GABA‐mediated inhibition of the anaphylactic response in the guinea‐pig trachea

Gentilini

Franchi‐Micheli

Mugnai

et al. 1995

British J Pharmacology

View full text Add to dashboard Cite

show abstract

“…It has been a long-standing belief that a GABAergic contribution to airway tone was largely mediated by GABA A channels in the brainstem (23) or GABA B channels on preganglionic cholinergic nerves in the lung (2,37). However, there is emerging evidence that a far more complex GABAergic system exists, which involves the presence of GABA channels not only nerves but also on airway epithelium and ASM itself (22,27,41).…”

Section: Discussionmentioning

confidence: 99%

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

Gallos¹,

Gleason²,

Zhang³

et al. 2008

American Journal of Physiology-Lung Cellular and Molecular Phys

View full text Add to dashboard Cite

Emala CW. Activation of endogenous GABAA channels on airway smooth muscle potentiates isoproterenol-mediated relaxation. Am J Physiol Lung Cell Mol Physiol 295: L1040 -L1047, 2008. First published September 12, 2008 doi:10.1152/ajplung.90330.2008.-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 GABAA channels on airway smooth muscle cells. We questioned whether endogenous GABAA channels on airway smooth muscle could augment ␤-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 GABAA antagonist gabazine (100 M), airway muscle was contracted with acetylcholine or ␤-ala neurokinin A, followed by relaxation induced by cumulatively increasing concentrations of isoproterenol (1 nM to 1 M) in the absence or presence of the selective GABAA agonist muscimol (10 -100 M). In separate experiments, guinea pig tracheal rings were pretreated with the large conductance KCa 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). GABAA 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 KCa channel. Selective activation of endogenous GABAA receptors significantly augments ␤-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 ASTHMA IS A CHRONIC inflammatory disease of the airways the prevalence of which both in the United States and throughout much of the world has taken on pandemic proportions (4). Standard treatment for asthma centers on pharmacological attenuation of hyperresponsiveness either by modulation of inflammatory mediators or by promoting airway smooth muscle (ASM) relaxation (e.g., ␤ 2 -adrenoceptor agonists). Although research over the past three decades has made great strides in elucidating many of the underlying mechanisms involved in this disease, few novel additions to the pharmacological armamentarium have occurred in the treatment of reactive airway disease.␤ 2 -Adrenoceptor agonists retain a prominent role in the clinical treatment of airway hyperresponsiveness, and the mechanisms by which ␤ 2 -adrenoceptor agonists relax ASM include both cAMP-dependent and cAMP-independent pathways. Additionally, regulation of ␤ 2 -adrenoceptor activity either through desensitization or downregu...

show abstract

“…Both volatile and intravenous anesthetics (which act on GABA A receptors) have long been known to dose dependently promote bronchodilation and attenuate bronchoconstriction, respectively. 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).…”

mentioning

confidence: 99%

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

Gallos

Yim

Chang

et al. 2012

American Journal of Physiology-Lung Cellular and Molecular Phys

View full text Add to dashboard Cite

The prevalence of asthma has taken on pandemic proportions. Since this disease predisposes patients to severe acute airway constriction, novel mechanisms capable of promoting airway smooth muscle relaxation would be clinically valuable. We have recently demonstrated that activation of endogenous airway smooth muscle GABAA receptors potentiates ␤-adrenoceptor-mediated relaxation, and molecular analysis of airway smooth muscle reveals that the ␣-subunit component of these GABAA receptors is limited to the ␣4-and ␣5-subunits. We questioned whether ligands with selective affinity for these GABAA receptors could promote relaxation of airway smooth muscle. RT-PCR analysis of GABAA receptor subunits was performed on RNA isolated by laser capture microdissection from human and guinea pig airway smooth muscle. Membrane potential and chloride-mediated current were measured in response to GABAA subunit-selective agonists in cultured human airway smooth muscle cells. Functional relaxation of precontracted guinea pig tracheal rings was assessed in the absence and presence of the ␣4-subunit-selective GABAA receptor agonists: gaboxadol, taurine, and a novel 8-methoxy imidazobenzodiazepine (CM-D-45). Only messenger RNA encoding the ␣4-and ␣5-GABAA receptor subunits was identified in RNA isolated by laser capture dissection from guinea pig and human airway smooth muscle tissues. Activation of airway smooth muscle GABAA receptors with agonists selective for these subunits resulted in appropriate membrane potential changes and chloride currents and promoted relaxation of airway smooth muscle. In conclusion, selective subunit targeting of endogenous airway smooth muscle-specific GABAA receptors may represent a novel therapeutic option for patients in severe bronchospasm.

show abstract

Prejunctional GABA-B inhibition of cholinergic, neurally-mediated airway contractions in guinea-pigs

Cited by 39 publications

References 26 publications

GABA‐mediated inhibition of the anaphylactic response in the guinea‐pig trachea

GABA‐mediated inhibition of the anaphylactic response in the guinea‐pig trachea

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

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

Contact Info

Product

Resources

About

Prejunctional GABA-B inhibition of cholinergic, neurally-mediated airway contractions in guinea-pigs

Cited by 39 publications

References 26 publications

GABA‐mediated inhibition of the anaphylactic response in the guinea‐pig trachea

GABA‐mediated inhibition of the anaphylactic response in the guinea‐pig trachea

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

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

Contact Info

Product

Resources

About

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

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