scholarly journals Endogenous γ-Aminobutyric Acid Modulates Tonic Guinea Pig Airway Tone and Propofol-induced Airway Smooth Muscle Relaxation

2009 ◽  
Vol 110 (4) ◽  
pp. 748-758 ◽  
Author(s):  
George Gallos ◽  
Neil R. Gleason ◽  
Laszlo Virag ◽  
Yi Zhang ◽  
Kentaro Mizuta ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Guinea Pig ◽  
Airway Smooth Muscle ◽  
Muscle Relaxation ◽  
Aminobutyric Acid ◽  
Smooth Muscle Relaxation ◽  
Airway Tone

S-nitrosoglutathione breakdown prevents airway smooth muscle relaxation in the guinea pig

2000 ◽  
Vol 279 (4) ◽  
pp. L716-L721 ◽  
Author(s):  
Kezhong Fang ◽  
Roger Johns ◽  
Timothy Macdonald ◽  
Michael Kinter ◽  
Benjamin Gaston
Keyword(s):  
Smooth Muscle ◽  
Guinea Pig ◽  
Airway Smooth Muscle ◽  
Muscle Tone ◽  
Muscle Relaxation ◽  
Tracheal Ring ◽  
Protein Fractions ◽  
Smooth Muscle Relaxation ◽  
Smooth Muscle Tone ◽  
Catabolic Activity

Airway levels of the endogenous bronchodilator S-nitrosoglutathione (GSNO) are low in children with near-fatal asthma. We hypothesized that GSNO could be broken down in the lung and that this catabolism could inhibit airway smooth muscle relaxation. In our experiments, GSNO was broken down by guinea pig lung homogenates, particularly after ovalbumin sensitization (OS). Two lung protein fractions had catabolic activity. One was NADPH dependent and was more active after OS. The other was NADPH independent and was partially inhibited by aurothioglucose. Guinea pig lung tissue protein fractions with GSNO catabolic activity inhibited GSNO-mediated guinea pig tracheal ring relaxation. The relaxant effect of GSNO was partially restored by aurothioglucose. These observations suggest that catabolism of GSNO in the guinea pig 1) is mediated by lung proteins, 2) is partially upregulated after OS, and 3) may contribute to increased airway smooth muscle tone. We speculate that enzymatic breakdown of GSNO in the lung could contribute to asthma pathophysiology by inhibiting the beneficial effects of GSNO, including its effect on airway smooth muscle tone.

scholarly journals GABAA receptors are expressed and facilitate relaxation in airway smooth muscle

2008 ◽  
Vol 294 (6) ◽  
pp. L1206-L1216 ◽  
Author(s):  
Kentaro Mizuta ◽  
Dingbang Xu ◽  
Yaping Pan ◽  
George Comas ◽  
Joshua R. Sonett ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Guinea Pig ◽  
Airway Smooth Muscle ◽  
Muscle Relaxation ◽  
Chronic Obstructive Lung Disease ◽  
Smooth Muscle Relaxation ◽  
Chronic Obstructive ◽  
Membrane Hyperpolarization ◽  
Time To Peak ◽  
Neuronal Inhibition

γ-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the mammalian central nervous system and exerts its actions via both ionotropic (GABAA) channels and metabotropic (GABAB) receptors. GABAA channels are ubiquitously expressed in neuronal tissues, and in mature neurons modulate an inward chloride current resulting in neuronal inhibition due to membrane hyperpolarization. In airway smooth muscle (ASM) cells, membrane hyperpolarization favors smooth muscle relaxation. Although GABAA channels and GABAB receptors have been functionally identified on peripheral nerves in the lung, GABAA channels have never been identified on ASM itself. We detected the mRNA encoding of the GABAA α4-, α5-, β3-, δ-, γ1–3-, π-, and θ-subunits in total RNA isolated from native human and guinea pig ASM and from cultured human ASM cells. Selected immunoblots identified the GABAA α4-, α5-, β3-, and γ2-subunit proteins in native human and guinea pig ASM and cultured human ASM cells. The GABAA β3-subunit protein was immunohistochemically localized to ASM in guinea pig tracheal rings. While muscimol, a specific GABAA channel agonist, did not affect the magnitude or the time to peak contractile effect of substance P, it directly concentration dependently relaxed a tachykinin-induced contraction in guinea pig tracheal rings, which was inhibited by the GABAA-selective antagonist gabazine. Muscimol also relaxed a contraction induced by an alternative contractile agonist histamine. These results demonstrate that functional GABAA channels are expressed on ASM and suggest a novel therapeutic target for the relaxation of ASM in diseases such as asthma and chronic obstructive lung disease.

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

2012 ◽  
Vol 302 (2) ◽  
pp. L248-L256 ◽  
Author(s):  
George Gallos ◽  
Peter Yim ◽  
Sucie Chang ◽  
Yi Zhang ◽  
Dingbang Xu ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Membrane Potential ◽  
Guinea Pig ◽  
Airway Smooth Muscle ◽  
Muscle Relaxation ◽  
Smooth Muscle Relaxation ◽  
Human Airway Smooth Muscle ◽  
Α Subunit ◽  
Human Airway ◽  
Laser Capture

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 β-adrenoceptor-mediated relaxation, and molecular analysis of airway smooth muscle reveals that the α-subunit component of these GABAA receptors is limited to the α4- and α5-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 α4-subunit-selective GABAA receptor agonists: gaboxadol, taurine, and a novel 8-methoxy imidazobenzodiazepine (CM-D-45). Only messenger RNA encoding the α4- and α5-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.

EETs relax airway smooth muscle via an EpDHF effect: BKCa channel activation and hyperpolarization

2001 ◽  
Vol 280 (5) ◽  
pp. L965-L973 ◽  
Author(s):  
Catherine Benoit ◽  
Barbara Renaudon ◽  
Dany Salvail ◽  
Eric Rousseau
Keyword(s):  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Molecular Mechanisms ◽  
Muscle Tone ◽  
Muscle Relaxation ◽  
Smooth Muscle Relaxation ◽  
Epoxyeicosatrienoic Acids ◽  
Bkca Channel ◽  
Channel Activity ◽  
Cytochrome P 450

Epoxyeicosatrienoic acids (EETs) are produced from arachidonic acid via the cytochrome P-450 epoxygenase pathway. EETs are able to modulate smooth muscle tone by increasing K+ conductance, hence generating hyperpolarization of the tissues. However, the molecular mechanisms by which EETs induce smooth muscle relaxation are not fully understood. In the present study, the effects of EETs on airway smooth muscle (ASM) were investigated using three electrophysiological techniques. 8,9-EET and 14,15-EET induced concentration-dependent relaxations of the ASM precontracted with a muscarinc agonist (carbamylcholine chloride), and these relaxations were partly inhibited by 10 nM iberiotoxin (IbTX), a specific large-conductance Ca2+-activated K+ (BKCa) channel blocker. Moreover, 3 μM 8,9- or 14,15-EET induced hyperpolarizations of −12 ± 3.5 and −16 ± 3 mV, with EC50 values of 0.13 and 0.14 μM, respectively, which were either reversed or blocked on addition of 10 nM IbTX. These results indicate that BKCa channels are involved in hyperpolarization and participate in the relaxation of ASM. In addition, complementary experiments demonstrated that 8,9- and 14,15-EET activate reconstituted BKCa channels at low free Ca2+ concentrations without affecting their unitary conductance. These increases in channel activity were IbTX sensitive and correlated well with the IbTX-sensitive hyperpolarization and relaxation of ASM. Together these results support the view that, in ASM, the EETs act through an epithelium-derived hyperpolarizing factorlike effect.

scholarly journals Opsin 3–Gαs Promotes Airway Smooth Muscle Relaxation Modulated by G Protein Receptor Kinase 2

2021 ◽  
Vol 64 (1) ◽  
pp. 59-68
Author(s):  
Amy D. Wu ◽  
William Dan ◽  
Yi Zhang ◽  
Shruti Vemaraju ◽  
Brian A. Upton ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
G Protein ◽  
Airway Smooth Muscle ◽  
Muscle Relaxation ◽  
Smooth Muscle Relaxation ◽  
Receptor Kinase ◽  
Protein Receptor

Basenji-greyhound dog: increased m2 muscarinic receptor expression in trachealis muscle

1995 ◽  
Vol 268 (6) ◽  
pp. L935-L940 ◽  
Author(s):  
C. W. Emala ◽  
A. Aryana ◽  
M. A. Levine ◽  
R. P. Yasuda ◽  
S. A. Satkus ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Adenylyl Cyclase ◽  
Muscarinic Receptor ◽  
Airway Smooth Muscle ◽  
Muscle Relaxation ◽  
Receptor Expression ◽  
Smooth Muscle Relaxation ◽  
Muscarinic Agonists ◽  
M2 Muscarinic Receptor ◽  
Muscarinic M2 Receptors

Airway smooth muscle from asthmatic humans and from the Basenji-greyhound dog (BG) dog is hyporesponsive to beta-adrenergic agonist stimulation. Because adenylyl cyclase is under dual regulation in airway smooth muscle, we compared muscarinic receptor-coupled inhibition of adenylyl cyclase in airway smooth muscle from BG and mongrel dogs. Inhibition of forskolin-stimulated adenylyl cyclase activity by the muscarinic M2 agonist oxotremorine was greater in airway smooth muscle membranes from BG compared with mongrel controls. Quantitative immunoprecipitation studies showed increased numbers of m2 but not m3 muscarinic receptors in the BG airway smooth muscle. The enhanced ability of muscarinic agonists to inhibit adenylyl cyclase in BG airway smooth muscle may be due to the greater numbers of muscarinic m2 receptors, which may account in part for impaired airway smooth muscle relaxation in the BG model of airway hyperresponsiveness.

G protein-coupled receptor kinase 5 regulates airway responses induced by muscarinic receptor activation

2004 ◽  
Vol 286 (2) ◽  
pp. L312-L319 ◽  
Author(s):  
J. K. L. Walker ◽  
R. R. Gainetdinov ◽  
D. S. Feldman ◽  
P. K. McFawn ◽  
M. G. Caron ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
G Protein ◽  
Muscarinic Receptor ◽  
Airway Smooth Muscle ◽  
Muscarinic Receptors ◽  
Muscle Relaxation ◽  
Receptor Activation ◽  
Smooth Muscle Relaxation ◽  
Airway Responses ◽  
G Protein Coupled

G protein-coupled receptors (GPCRs) transduce extracellular signals into intracellular events. The waning responsiveness of GPCRs in the face of persistent agonist stimulation, or desensitization, is a necessary event that ensures physiological homeostasis. GPCR kinases (GRKs) are important regulators of GPCR desensitization. GRK5, one member of the GRK family, desensitizes central M2 muscarinic receptors in mice. We questioned whether GRK5 might also be an important regulator of peripheral muscarinic receptor responsiveness in the cardiopulmonary system. Specifically, we wanted to determine the role of GRK5 in regulating muscarinic receptor-mediated control of airway smooth muscle tone or regulation of cholinergic-induced bradycardia. Tracheal pressure, heart rate, and tracheal smooth muscle tension were measured in mice having a targeted deletion of the GRK5 gene ( GRK5- /-) and littermate wild-type (WT) control mice. Both in vivo and in vitro results showed that the airway contractile response to a muscarinic receptor agonist was not different between GRK5- /- and WT mice. However, the relaxation component of bilateral vagal stimulation and the airway smooth muscle relaxation resulting from β2-adrenergic receptor activation were diminished in GRK5- /- mice. These data suggest that M2 muscarinic receptor-mediated opposition of airway smooth muscle relaxation is regulated by GRK5 and is, therefore, excessive in GRK5- /- mice. In addition, this study shows that GRK5 regulates pulmonary responses in a tissue- and receptor-specific manner but does not regulate peripheral cardiac muscarinic receptors. GRK5 regulation of airway responses may have implications in obstructive airway diseases such as asthma or chronic obstructive pulmonary disease.

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