Cyclooxygenase inhibitors increase canine tracheal muscle response to parasympathetic stimuli in situ

1990 ◽  
Vol 68 (6) ◽  
pp. 2597-2603 ◽  
Author(s):  
R. A. Bethel ◽  
C. L. McClure
Keyword(s):  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Cyclooxygenase Inhibitors ◽  
Muscarinic Agonist ◽  
Vagus Nerves ◽  
Lipoxygenase Inhibitor ◽  
Mediators Of Inflammation ◽  
Parasympathetic Control

To determine whether cyclooxygenase inhibitors alter parasympathetic control of airway smooth muscle in situ, we pretreated anesthetized dogs with intravenous indomethacin, meclofenamate, or normal saline and measured the isometric contraction of tracheal muscle in response to electrical stimulation of the vagus nerves. Indomethacin and meclofenamate increase the response of airway smooth muscle to parasympathetic stimulation. In subsequent experiments to determine the site of action of cyclooxygenase inhibitors, we found that indomethacin does not alter the response of tracheal muscle to intra-arterial acetylcholine (a muscarinic agonist) but does augment the response to intra-arterial dimethylpiperaziniumiodide (a nicotinic agonist). Moreover, the response to parasympathetic stimulation after pretreatment with a combination of indomethacin and BW755C (a combined cyclooxygenase-lipoxygenase inhibitor) does not differ significantly from the response after indomethacin or meclofenamate alone. We conclude that cyclooxygenase inhibitors increase the sensitivity of the contractile response of tracheal smooth muscle to parasympathetic stimulation, that they exert their effect on the postganglionic parasympathetic neuron, and that their effect is prejunctional. The effect appears secondary to a decrease in cyclooxygenase products rather than to an increase in lipoxygenase products. These findings suggest that endogenous cyclooxygenase products may modulate parasympathetic control of airway smooth muscle in vivo. They may relate to the mechanisms that underlie airway hyperresponsiveness, by which mediators of inflammation modulate airway responsiveness and by which nonsteroidal anti-inflammatory drugs induce severe bronchoconstrictor responses in some persons who have asthma.

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.

scholarly journals Methacholine causes reflex bronchoconstriction

1999 ◽  
Vol 86 (1) ◽  
pp. 294-297 ◽  
Author(s):  
Elizabeth M. Wagner ◽  
David B. Jacoby
Keyword(s):  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Bronchial Artery ◽  
Muscle Tension ◽  
Reflex Response ◽  
Resistance Change ◽  
Bilateral Vagotomy ◽  
Airways Resistance ◽  
Lower Airways

To determine whether methacholine causes vagally mediated reflex constriction of airway smooth muscle, we administered methacholine to sheep either via the bronchial artery or as an aerosol via tracheostomy into the lower airways. We then measured the contraction of an isolated, in situ segment of trachealis smooth muscle and determined the effect of vagotomy on the trachealis response. Administering methacholine to the subcarinal airways via the bronchial artery (0.5–10.0 μg/ml) caused dose-dependent bronchoconstriction and contraction of the tracheal segment. At the highest methacholine concentration delivered, trachealis smooth muscle tension increased an average of 186% over baseline. Aerosolized methacholine (5–7 breaths of 100 mg/ml) increased trachealis tension by 58% and airways resistance by 183%. As the bronchial circulation in the sheep does not supply the trachea, we postulated that the trachealis contraction was caused by a reflex response to methacholine in the lower airways. Bilateral vagotomy essentially eliminated the trachealis response and the airways resistance change after lower airways challenge (either via the bronchial artery or via aerosol) with methacholine. We conclude that 1) methacholine causes a substantial reflex contraction of airway smooth muscle and 2) the assumption may not be valid that a response to methacholine in humans or experimental animals represents solely the direct effect on smooth muscle.

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.

Characterization of the airway smooth muscle muscarinic receptor in vivo

1991 ◽  
Vol 197 (1-2) ◽  
pp. 109-112 ◽  
Author(s):  
Ralph E. Howell ◽  
Keith Laemont ◽  
Raymond Gaudette ◽  
Maureen Raynor ◽  
Abby Warner ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Muscarinic Receptor ◽  
Airway Smooth Muscle

Mechanism of partial adaptation in airway smooth muscle after a step change in length

2007 ◽  
Vol 103 (2) ◽  
pp. 569-577 ◽  
Author(s):  
Farah Ali ◽  
Leslie Chin ◽  
Peter D. Paré ◽  
Chun Y. Seow
Keyword(s):  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Intermediate State ◽  
Ultrastructural Changes ◽  
Myosin Filament ◽  
Shortening Velocity ◽  
Myosin Filaments ◽  
Partial Adaptation ◽  
Static Conditions

The phenomenon of length adaptation in airway smooth muscle (ASM) is well documented; however, the underlying mechanism is less clear. Evidence to date suggests that the adaptation involves reassembly of contractile filaments, leading to reconfiguration of the actin filament lattice and polymerization or depolymerization of the myosin filaments within the lattice. The time courses for these events are unknown. To gain insights into the adaptation process, we examined ASM mechanical properties and ultrastructural changes during adaptation. Step changes in length were applied to isolated bundles of ASM cells; changes in force, shortening velocity, and myosin filament mass were then quantified. A greater decrease in force was found following an acute decrease in length, compared with that of an acute increase in length. A decrease in myosin filament mass was also found with an acute decrease in length. The shortening velocity measured immediately after the length change was the same as that measured after the muscle had fully adapted to the new length. These observations can be explained by a model in which partial adaptation of the muscle leads to an intermediate state in which reconfiguration of the myofilament lattice occurred rapidly, followed by a relatively slow process of polymerization of myosin filaments within the lattice. The partially adapted intermediate state is perhaps more physiologically relevant than the fully adapted state seen under static conditions, and it simulates a more realistic behavior for ASM in vivo.

Leukotriene D4 induces MMP-1, which functions as an IGFBP protease in human airway smooth muscle cells

1996 ◽  
Vol 271 (6) ◽  
pp. L1014-L1022 ◽  
Author(s):  
R. Rajah ◽  
S. E. Nunn ◽  
D. J. Herrick ◽  
M. M. Grunstein ◽  
P. Cohen
Keyword(s):  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Airway Smooth Muscle Cells ◽  
Igf Binding Proteins ◽  
Leukotriene D4 ◽  
Igf Binding ◽  
Dose Dependent Increase ◽  
Dose Dependent ◽  
Insulin Like Growth Factors

We have previously demonstrated that the asthma-associated proinflammatory eicosanoid leukotriene D4 (LTD4) is comitogenic with insulin-like growth factors (IGF) in airway smooth muscle (ASM) cells. This synergistic effect of LTD4 and IGF on ASM cell growth involves proteolysis of ASM-produced inhibitory IGF-binding proteins (IGFBP). In this report, we analyzed the conditioned media (CM) from LTD4-treated human ASM cells (ASM-LTD4-CM) by Western ligand blotting and demonstrated a marked LTD4-induced reduction in the levels of the intact IGFBP (predominantly IGFBP-2) secreted by these cells. The IGFBP-2 in the ASM-LTD4-CM was identified as lower-molecular-weight fragments by Western immunoblotting. Incubation with 125I-labeled IGFBP demonstrated that an IGFBP protease was induced in the ASM cells in response to LTD4 treatment. Immunodepletion of ASM-LTD4-CM with anti-matrix metalloproteinase (MMP)-1 antibodies demonstrated a dose-dependent reduction of IGFBP proteolysis. Tissue inhibitor of MMP-1 and Batimastat (synthetic) inhibited proteolysis of IGFBP. Immunoblotting the ASM-LTD4-CM with anti-MMP-1 demonstrated a dose-dependent increase in MMP-1 protein. Similar results were also obtained by immunocytochemistry. Collectively, these observations demonstrate that MMP-1 is an IGFBP protease induced by leukotrienes that plays a significant role in modulating IGF action in ASM cells. A similar mechanism may be applicable in vivo in the airways of patients with asthma.

Contributions of arachidonic acid derivatives and substance P to the sensitization of cutaneous nociceptors

1990 ◽  
Vol 64 (2) ◽  
pp. 457-464 ◽  
Author(s):  
R. H. Cohen ◽  
E. R. Perl
Keyword(s):  
Arachidonic Acid ◽  
Substance P ◽  
Receptive Fields ◽  
Lipoxygenase Inhibitor ◽  
Arterial Perfusion ◽  
Mediators Of Inflammation ◽  
Rabbit Ear ◽  
C Fiber

1. The role of presumed chemical mediators of inflammation in the heat-induced sensitization of cutaneous C-polymodal nociceptors (CPNs) was examined in a rabbit ear preparation maintained in vitro by intra-arterial perfusion with a solution free of protein and cellular elements. 2. In this preparation, CPNs consistently showed enhanced responsiveness after repeated exposure of their receptive fields to noxious levels of heat. The average magnitude of sensitization was quantitatively similar to that observed in vivo, suggesting that blood-born factors are not essential for development of sensitization. 3. Sensitization in one-half of randomly selected CPNs was blocked or reduced when the perfusate contained a cyclooxygenase inhibitor, indomethacin or dipyrone, or the dual cyclooxygenase/lipoxygenase inhibitor, BW755C, even though initial responsiveness to heat and pressure was unaltered. These observations suggest that arachidonic acid breakdown products, possibly prostaglandins, are intermediaries in the sensitization of some, but not all, C-fiber nociceptors of the skin. In addition, heat-induced sensitization for some C-fiber cutaneous nociceptors is the result of processes that are at least partially independent of those involved in excitation. 4. Substance P (SP) or the putative SP antagonists, [D-Pro2, D-Trp7.9]-SP or [D-Pro2, D-Phe7, D-Trip9]-SP, produced no significant effect on heat-responsiveness or sensitization, although ongoing activity may have marginally increased over control levels after repeated heat stimulations. We conclude that SP in an in vitro preparation is not involved in the enhancement of cutaneous C-fiber nociceptor responsiveness after repeated thermal insults.

scholarly journals In vitro, in silico and in vivo study challenges the impact of bronchial thermoplasty on acute airway smooth muscle mass loss

2018 ◽  
Vol 51 (5) ◽  
pp. 1701680 ◽  
Author(s):  
Igor L. Chernyavsky ◽  
Richard J. Russell ◽  
Ruth M. Saunders ◽  
Gavin E. Morris ◽  
Rachid Berair ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Asthma Control ◽  
Muscle Mass ◽  
Airway Smooth Muscle ◽  
In Silico ◽  
Heat Distribution ◽  
Airway Wall ◽  
Epithelial Integrity

Bronchial thermoplasty is a treatment for asthma. It is currently unclear whether its histopathological impact is sufficiently explained by the proportion of airway wall that is exposed to temperatures necessary to affect cell survival.Airway smooth muscle and bronchial epithelial cells were exposed to media (37–70°C) for 10 s to mimic thermoplasty. In silico we developed a mathematical model of airway heat distribution post-thermoplasty. In vivo we determined airway smooth muscle mass and epithelial integrity pre- and post-thermoplasty in 14 patients with severe asthma.In vitro airway smooth muscle and epithelial cell number decreased significantly following the addition of media heated to ≥65°C. In silico simulations showed a heterogeneous heat distribution that was amplified in larger airways, with <10% of the airway wall heated to >60°C in airways with an inner radius of ∼4 mm. In vivo at 6 weeks post-thermoplasty, there was an improvement in asthma control (measured via Asthma Control Questionnaire-6; mean difference 0.7, 95% CI 0.1–1.3; p=0.03), airway smooth muscle mass decreased (absolute median reduction 5%, interquartile range (IQR) 0–10; p=0.03) and epithelial integrity increased (14%, IQR 6–29; p=0.007). Neither of the latter two outcomes was related to improved asthma control.Integrated in vitro and in silico modelling suggest that the reduction in airway smooth muscle post-thermoplasty cannot be fully explained by acute heating, and nor did this reduction confer a greater improvement in asthma control.

Sign in / Sign up

Export Citation Format

Share Document