scholarly journals Sympathetic nerve-dependent regulation of mucosal vascular tone modifies airway smooth muscle reactivity

2010 ◽  
Vol 109 (5) ◽  
pp. 1292-1300 ◽  
Author(s):  
Stuart B. Mazzone ◽  
Lina H. K. Lim ◽  
Elizabeth M. Wagner ◽  
Nanako Mori ◽  
Brendan J. Canning
Keyword(s):  
Blood Flow ◽  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Vascular Function ◽  
Adrenergic Receptor ◽  
Muscle Tone ◽  
Mucosal Blood Flow ◽  
Nerve Fibers ◽  
Neurokinin A

The airways contain a dense subepithelial microvascular plexus that is involved in the supply and clearance of substances to and from the airway wall. We set out to test the hypothesis that airway smooth muscle reactivity to bronchoconstricting agents may be dependent on airway mucosal blood flow. Immunohistochemical staining identified vasoconstrictor and vasodilator nerve fibers associated with subepithelial blood vessels in the guinea pig airways. Intravital microscopy of the tracheal mucosal microvasculature in anesthetized guinea pigs revealed that blockade of α-adrenergic receptors increased baseline arteriole diameter by ∼40%, whereas the α-adrenergic receptor agonist phenylephrine produced a modest (5%) vasoconstriction in excess of the baseline tone. In subsequent in vivo experiments, tracheal contractions evoked by topically applied histamine were significantly reduced ( P < 0.05) and enhanced by α-adrenergic receptor blockade and activation, respectively. α-Adrenergic ligands produced similar significant ( P < 0.05) effects on airway smooth muscle contractions evoked by topically administered capsaicin, intravenously administered neurokinin A, inhaled histamine, and topically administered antigen in sensitized animals. These responses were independent of any direct effect of α-adrenergic ligands on the airway smooth muscle tone. The data suggest that changes in blood flow in the vessels supplying the airways regulate the reactivity of the underlying airway smooth muscle to locally released and exogenously administered agents by regulating their clearance. We speculate that changes in mucosal vascular function or changes in neuronal regulation of the airway vasculature may contribute to airways responsiveness in disease.

Inhibition of dihydropyridine-sensitive calcium entry in hypoxic relaxation of airway smooth muscle

1995 ◽  
Vol 268 (2) ◽  
pp. L201-L206 ◽  
Author(s):  
C. Vannier ◽  
T. L. Croxton ◽  
L. S. Farley ◽  
C. A. Hirshman
Keyword(s):  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Muscle Tone ◽  
Bay K 8644 ◽  
O2 Concentration ◽  
Voltage Dependent ◽  
Progressive Hypoxia ◽  
Carbamyl Choline

Hypoxia dilates airways in vivo and reduces active tension of airway smooth muscle in vitro. To determine whether hypoxia impairs Ca2+ entry through voltage-dependent channels (VDC), we tested the ability of dihydropyridines to modulate hypoxia-induced relaxation of KCl- and carbamyl choline (carbachol)-contracted porcine bronchi. Carbachol- or KCl-contracted bronchial rings were exposed to progressive hypoxia in the presence or absence of 1 microM BAY K 8644 (an L-type-channel agonist). In separate experiments, rings were contracted with carbachol or KCl, treated with nifedipine (a VDC antagonist), and finally exposed to hypoxia. BAY K 8644 prevented hypoxia-induced relaxation in KCl-contracted bronchi. Nifedipine (10(-5) M) totally relaxed KCl- contracted bronchi. Carbachol-contracted bronchi were only partially relaxed by nifedipine but were completely relaxed when the O2 concentration of the gas was reduced from 95 to 0%. These data indicate that hypoxia can reduce airway smooth muscle tone by limiting entry of Ca2+ through a dihydropyridine-sensitive pathway, but that other mechanisms also contribute to hypoxia-induced relaxation of carbachol-contracted bronchi.

Airway smooth muscle tone increases airway responsiveness in healthy young adults

2017 ◽  
Vol 312 (3) ◽  
pp. L348-L357 ◽  
Author(s):  
Morgan Gazzola ◽  
Katherine Lortie ◽  
Cyndi Henry ◽  
Samuel Mailhot-Larouche ◽  
David G. Chapman ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Muscle Tone ◽  
Airway Responsiveness ◽  
High Dose ◽  
Forced Oscillation Technique ◽  
Single High Dose ◽  
Healthy Humans

Force adaptation, a process whereby sustained spasmogenic activation (viz., tone) of airway smooth muscle (ASM) increases its contractile capacity, has been reported in isolated ASM tissues in vitro, as well as in mice in vivo. The objective of the present study was to assess the effect of tone on airway responsiveness in humans. Ten healthy volunteers underwent methacholine challenge on two occasions. One challenge consisted of six serial doses of saline followed by a single high dose of methacholine. The other consisted of six low doses of methacholine 5 min apart followed by a higher dose. The cumulative dose was identical for both challenges. After both methacholine challenges, subjects took a deep inspiration (DI) to total lung capacity as another way to probe ASM mechanics. Responses to methacholine and the DI were measured using a multifrequency forced oscillation technique. Compared with a single high dose, the challenge preceded by tone led to an elevated response measured by respiratory system resistance (Rrs) and reactance at 5 Hz. However, there was no difference in the increase in Rrs at 19 Hz, suggesting a predominant effect on smaller airways. Increased tone also reduced the efficacy of DI, measured by an attenuated maximal dilation during the DI and an increased renarrowing post-DI. We conclude that ASM tone increases small airway responsiveness to inhaled methacholine and reduces the effectiveness of DI in healthy humans. This suggests that force adaptation may contribute to airway hyperresponsiveness and the reduced bronchodilatory effect of DI in asthma.

Halothane Does Not Inhibit the Functional Coupling between the β2-Adrenergic Receptor and the GαsHeterotrimeric G Protein

2006 ◽  
Vol 104 (4) ◽  
pp. 754-762
Author(s):  
Masao Hayashi ◽  
Sumedha G. Penheiter ◽  
Tetsuzo Nakayama ◽  
Alan R. Penheiter ◽  
David O. Warner ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Adrenergic Receptor ◽  
Minimum Alveolar Concentration ◽  
Calcium Sensitivity ◽  
Functional Coupling ◽  
Nucleotide Exchange ◽  
Β2 Adrenergic Receptor ◽  
In Vivo Animal Models

Background This study investigated whether halothane affects the functional coupling between the beta2 adrenergic receptor and the alpha subunit of its cognate stimulatory heterotrimeric guanosine-5'-triphosphate (GTP)-binding protein (Galphas). The authors hypothesized that halothane does not affect isoproterenol-promoted guanosine nucleotide exchange at Galphas and hence would not affect isoproterenol-induced relaxation of airway smooth muscle. Methods Halothane effects on isoproterenol-induced inhibition of calcium sensitivity were measured in permeabilized porcine airway smooth muscle. Galphas nucleotide exchange was measured in crude membranes prepared from COS-7 cells transfected to transiently coexpress the human beta1 or beta2 receptor each with human short Galphas. A radioactive, nonhydrolyzable analog of GTP, [S]GTPgammaS, was used as the reporter for nucleotide exchange at Galphas. Results Halothane (0.75 mm, approximately 2.8 minimum alveolar concentration [MAC] in pigs) did not affect isoproterenol-induced inhibition of calcium sensitivity. Isoproterenol caused a time- and concentration-dependent increase in Galphas nucleotide exchange. Halothane, even at concentrations of 1.5 mm (approximately 5.6 MAC), had no effect on basal Galphas nucleotide exchange in the absence of isoproterenol, whereas halothane inhibited isoproterenol-promoted Galphas nucleotide exchange in both the beta1-Galphas and beta2-Galphas expressing membranes. However, the effect was significantly greater on beta1-Galphas coupling compared with beta2-Galphas coupling, with no effect on beta2-Galphas coupling at 2.8 MAC halothane. Conclusion Halothane does not inhibit the biochemical coupling between the beta2 receptor and Galphas and hence does not affect the inhibition of calcium sensitivity induced by isoproterenol. Therefore, halothane should not affect the efficacy of beta2 agonists, as suggested by studies of in vivo animal models of asthma.

scholarly journals Expression and coupling of neurokinin receptor subtypes to inositol phosphate and calcium signaling pathways in human airway smooth muscle cells

2008 ◽  
Vol 294 (3) ◽  
pp. L523-L534 ◽  
Author(s):  
Kentaro Mizuta ◽  
George Gallos ◽  
Defen Zhu ◽  
Fumiko Mizuta ◽  
Farida Goubaeva ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Substance P ◽  
Calcium Signaling ◽  
Airway Smooth Muscle ◽  
Inositol Phosphate ◽  
Nerve Fibers ◽  
Neurokinin A ◽  
Human Airway Smooth Muscle ◽  
Human Airway ◽  
Intracellular Ca

Neuropeptide tachykinins (substance P, neurokinin A, and neurokinin B) are present in peripheral terminals of sensory nerve fibers within the respiratory tract and cause airway contractile responses and hyperresponsiveness in humans and most mammalian species. Three subtypes of neurokinin receptors (NK1R, NK2R, and NK3R) classically couple to Gq protein-mediated inositol 1,4,5-trisphosphate (IP3) synthesis and liberation of intracellular Ca2+, which initiates contraction, but their expression and calcium signaling mechanisms are incompletely understood in airway smooth muscle. All three subtypes were identified in native and cultured human airway smooth muscle (HASM) and were subsequently overexpressed in HASM cells using a human immunodeficiency virus-1-based lentivirus transduction system. Specific NKR agonists {NK1R, [Sar9,Met(O2)11]-substance P; NK2R, [β-Ala8]-neurokinin A(4–10); NK3R, senktide} stimulated inositol phosphate synthesis and increased intracellular Ca2+ concentration ([Ca2+]i) in native HASM cells and in HASM cells transfected with each NKR subtype. These effects were blocked by NKR-selective antagonists (NK1R, L-732138; NK2R, GR-159897; NK3R, SB-222200). The initial transient and sustained phases of increased [Ca2+]i were predominantly inhibited by the IP3 receptor antagonist 2-aminoethoxydiphenyl borate (2-APB) or the store-operated Ca2+ channel antagonist SKF-96365, respectively. These results show that all three subtypes of NKRs are expressed in native HASM cells and that IP3 levels are the primary mediators of NKR-stimulated initial [Ca2+]i increases, whereas store-operated Ca2+ channels mediate the sustained phase of the [Ca2+]i increase.

Invited Review: Complexity of factors modulating airway narrowing in vivo: relevance to assessment of airway hyperresponsiveness

2003 ◽  
Vol 95 (3) ◽  
pp. 1305-1313 ◽  
Author(s):  
Vito Brusasco ◽  
Riccardo Pellegrino
Keyword(s):  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Muscle Activation ◽  
Muscle Tone ◽  
Clinical Settings ◽  
Airway Narrowing ◽  
Geometric Factors ◽  
Airway Caliber ◽  
Airway Response

In vivo, the airway response to constrictor stimuli is the net result of a complex array of factors, some facilitating and some opposing airway narrowing, which makes the interpretation of bronchial challenges far from being straightforward. This review begins with a short description of the complex mechanisms of airway smooth muscle activation and force generation as the starting events for airway narrowing. It then focuses on gain factors modulating airway smooth muscle shortening and on the geometric factors determining the magnitude of reduction in airway caliber in vivo. Finally, in light of the evidence that mechanical modulation of airway smooth muscle tone and airway narrowing is at least as important as the inflammatory contractile mediators in the pathogenesis of airway hyper-responsiveness, the implications for the interpretation of bronchial challenges in clinical settings are discussed.

Localization of cholinergic nerves in lower airways of guinea pigs using antisera to choline acetyltransferase

1997 ◽  
Vol 272 (4) ◽  
pp. L731-L738 ◽  
Author(s):  
B. J. Canning ◽  
A. Fischer
Keyword(s):  
Smooth Muscle ◽  
Nerve Cell ◽  
Lamina Propria ◽  
Airway Smooth Muscle ◽  
Choline Acetyltransferase ◽  
Muscle Tone ◽  
Nerve Fibers ◽  
Specific Marker ◽  
Cholinergic Nerves ◽  
Peripheral Airways

Primary antiserum to choline acetyltransferase (ChAT), a specific marker for cholinergic nerves, was used to characterize the distribution of cholinergic nerve fibers and nerve cell bodies in guinea pig airways. ChAT immunoreactive nerve fibers were localized to the smooth muscle throughout the conducting airways and in the lamina propria of the trachea and large bronchi. Likewise, all nerve cell bodies in the ganglia intrinsic to the trachea and bronchi displayed a cholinergic phenotype. By contrast, ChAT immunoreactive nerve fibers were infrequently seen in the lamina propria of the peripheral airways and were absent in the airway epithelium. No evidence for colocalization of ChAT and the enzyme synthesizing the putative relaxant neurotransmitter nitric oxide was observed. These results provide further evidence for the key role played by cholinergic nerves in regulating airway smooth muscle tone and bronchial blood flow and provide further evidence that acetylcholine is not coreleased with the neurotransmitter(s) mediating relaxations of airway smooth muscle.

scholarly journals Agonism of the TMEM16A calcium-activated chloride channel modulates airway smooth muscle tone

2020 ◽  
Vol 318 (2) ◽  
pp. L287-L295 ◽  
Author(s):  
Jennifer Danielsson ◽  
Aisha S. Kuforiji ◽  
Gene T. Yocum ◽  
Yi Zhang ◽  
Dingbang Xu ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Chloride Channel ◽  
Airway Resistance ◽  
Muscle Tone ◽  
Ex Vivo ◽  
Organ Bath ◽  
Novel Therapies ◽  
In Vivo Models

TMEM16A (anoctamin 1) is an important calcium-activated chloride channel in airway smooth muscle (ASM). We have previously shown that TMEM16A antagonists such as benzbromarone relax ASM and have proposed TMEM16A antagonists as novel therapies for asthma treatment. However, TMEM16A is also expressed on airway epithelium, and TMEM16A agonists are being investigated as novel therapies for cystic fibrosis. There are theoretical concerns that agonism of TMEM16A on ASM could lead to bronchospasm, making them detrimental as airway therapeutics. The TMEM16A agonist Eact induced a significant contraction of human ASM and guinea pig tracheal rings in an ex vivo organ bath model. Pretreatment with two different TMEM16A antagonists, benzbromarone or T16Ainh-A01, completely attenuated these Eact-induced contractions. Pretreatment with Eact alone augmented the maximum acetylcholine contraction. Pretreatment of A/J mice in vivo with nebulized Eact caused an augmentation of methacholine-induced increases in airway resistance measured by the forced oscillatory technique (flexiVent). Pretreatment with the TMEM16A antagonist benzbromarone significantly attenuated methacholine-induced increases in airway resistance. In in vitro cellular studies, TMEM16A was found to be expressed more abundantly in ASM compared with epithelial cells in culture (8-fold higher in ASM). Eact caused an increase in intracellular calcium in human ASM cells that was completely attenuated by pretreatment with benzbromarone. Eact acutely depolarized the plasma membrane potential of ASM cells, which was attenuated by benzbromarone or nifedipine. The TMEM16A agonist Eact modulates ASM contraction in both ex vivo and in vivo models, suggesting that agonism of TMEM16A may lead to clinically relevant bronchospasm.

scholarly journals Tidal volume amplitude affects the degree of induced bronchoconstriction in dogs

1999 ◽  
Vol 87 (5) ◽  
pp. 1674-1677 ◽  
Author(s):  
Francesco G. Salerno ◽  
Norihiro Shinozuka ◽  
Jeffrey J. Fredberg ◽  
Mara S. Ludwig
Keyword(s):  
Smooth Muscle ◽  
Tidal Volume ◽  
Airway Smooth Muscle ◽  
Muscle Tone ◽  
Main Bronchus ◽  
Canine Model ◽  
Smooth Muscle Contraction ◽  
Double Lumen Endotracheal Tube ◽  
The Difference

When isolated constricted airway smooth muscle is oscillated, muscle tone decreases. We investigated whether changing tidal volume (Vt) would affect induced bronchoconstriction in an in vivo canine model. Open-chest dogs were intubated with a double-lumen endotracheal tube, which isolated each main bronchus, and mechanically ventilated with a dual-cylinder ventilator. Bronchial pressure (Pbr) and flow were measured separately in each lung. Resistance and elastance were calculated by fitting the changes in Pbr, flow, and volume to the equation of motion. After baseline measurements at the same Vt (150 ml), the two lungs were ventilated with different Vt (50 vs. 250 ml) at a constant positive end-expiratory pressure. A continuous infusion of methacholine was begun, and measurements were repeated. The two lungs were then ventilated with the same Vt (250 ml), and measurements were again repeated. A similar protocol was performed in a second group of dogs in which mean Pbr was kept constant. Bronchoconstriction was more severe in the lung ventilated with lower Vt in both protocols. When Vt was reset to the same amplitude in the two lungs, the difference in bronchoconstriction was abrogated. These results demonstrate that large Vt inhibits airway smooth muscle contraction, regardless of mean Pbr.

Development and maintenance of force and stiffness in airway smooth muscle

2015 ◽  
Vol 93 (3) ◽  
pp. 163-169 ◽  
Author(s):  
Bo Lan ◽  
Brandon A. Norris ◽  
Jeffrey C.-Y. Liu ◽  
Peter D. Paré ◽  
Chun Y. Seow ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Smooth Muscle ◽  
Solid State ◽  
Airway Smooth Muscle ◽  
Deep Inspiration ◽  
Contractile Apparatus ◽  
Tidal Breathing ◽  
Actomyosin Interaction ◽  
Filament Network

Airway smooth muscle (ASM) plays a central role in the excessive narrowing of the airway that characterizes the primary functional impairment in asthma. This phenomenon is known as airway hyper-responsiveness (AHR). Emerging evidence suggests that the development and maintenance of ASM force involves dynamic reorganization of the subcellular filament network in both the cytoskeleton and the contractile apparatus. In this review, evidence is presented to support the view that regulation of ASM contraction extends beyond the classical actomyosin interaction and involves processes within the cytoskeleton and at the interfaces between the cytoskeleton, the contractile apparatus, and the extracellular matrix. These processes are initiated when the muscle is activated, and collectively they cause the cytoskeleton and the contractile apparatus to undergo structural transformation, resulting in a more connected and solid state that allows force generated by the contractile apparatus to be transmitted to the extracellular domain. Solidification of the cytoskeleton also serves to stiffen the muscle and hence the airway. Oscillatory strain from tidal breathing and deep inspiration is believed to be the counter balance that prevents hypercontraction and stiffening of ASM in vivo. Dysregulation of this balance could lead to AHR seen in asthma.

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