In vitro studies on the interactions of β2-adrenoceptor agonists, methylxanthines, Ca2+-channel blockers, K+-channel openers and other airway smooth muscle relaxants in isolated guinea-pig trachea

Airway smooth muscle plasma membranes contain a variety of functional K+ channels. In particular, there is a predominance of Ca(2+)-activated K+ channels (maxi-K). Inhibition of these K+ channels has been postulated to account for the ability of charybdotoxin (ChTX) to produce contraction of airway smooth muscle and to modify the relaxant effects of beta-adrenoceptor agonists and sodium nitroprusside (SNP). Iberiotoxin (IbTX) is more selective and more potent than ChTX at blocking maxi-K channels. In this study, pharmacological experiments were performed on guinea pig trachea to determine whether IbTX produced effects similar to ChTX. The concentration-response curves to salbutamol were markedly affected by IbTX, with a > 60-fold rightward shift being produced with 20 nM IbTX. The maximal relaxation to salbutamol was reduced to 49.3 +/- 0.9, 22.3 +/- 4.7, and 15.0 +/- 2.7% of control maximum in the presence of 20, 60, and 180 nM IbTX, respectively. Similar to salbutamol, the maximal relaxation to SNP was reduced to 80 +/- 1.6, 19 +/- 1.7, and 12 +/- 2.1% of control maximum in the presence of 20, 60, and 180 nM IbTX, respectively. IbTX (180 nM) failed to produce a significant alteration of relaxation to the ATP-dependent K+ channel agonist BRL-34915. Exposure of tissues to K(+)-rich medium (80 mM) inhibited responses to salbutamol > or = SNP > isoproterenol. These results confirm and extend our earlier observations that maxi-K channels may be involved in regulating tone and relaxation of carbachol-contracted guinea pig tracheal smooth muscle. This mechanism is of particular importance for beta 2-adrenoceptor- and SNP-induced relaxation.

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The Strain on Airway Smooth Muscle During a Deep Inspiration to Total Lung Capacity

Journal of Engineering and Science in Medical Diagnostics and Therapy ◽

10.1115/1.4042309 ◽

2019 ◽

Vol 2 (1) ◽

Cited By ~ 1

Author(s):

Ynuk Bossé

Keyword(s):

Smooth Muscle ◽

Airway Smooth Muscle ◽

Total Lung Capacity ◽

In Vitro Studies ◽

Deep Inspiration ◽

Bronchodilator Effect ◽

Lung Capacity ◽

Residual Capacity

The deep inspiration (DI) maneuver entices a great deal of interest because of its ability to temporarily ease the flow of air into the lungs. This salutary effect of a DI is proposed to be mediated, at least partially, by momentarily increasing the operating length of airway smooth muscle (ASM). Concerningly, this premise is largely derived from a growing body of in vitro studies investigating the effect of stretching ASM by different magnitudes on its contractility. The relevance of these in vitro findings remains uncertain, as the real range of strains ASM undergoes in vivo during a DI is somewhat elusive. In order to understand the regulation of ASM contractility by a DI and to infer on its putative contribution to the bronchodilator effect of a DI, it is imperative that in vitro studies incorporate levels of strains that are physiologically relevant. This review summarizes the methods that may be used in vivo in humans to estimate the strain experienced by ASM during a DI from functional residual capacity (FRC) to total lung capacity (TLC). The strengths and limitations of each method, as well as the potential confounders, are also discussed. A rough estimated range of ASM strains is provided for the purpose of guiding future in vitro studies that aim at quantifying the regulatory effect of DI on ASM contractility. However, it is emphasized that, owing to the many limitations and confounders, more studies will be needed to reach conclusive statements.

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In-vitro exposure of guinea pig main bronchi to 2·5 ppm of nitrogen dioxide does not alter airway smooth muscle response

Respiratory Medicine ◽

10.1016/0954-6111(95)90002-0 ◽

1995 ◽

Vol 89 (5) ◽

pp. 323-328 ◽

Cited By ~ 5

Author(s):

P. Chitano ◽

R.E. Lucchini ◽

E. Coser ◽

A. Papi ◽

M. Saetta ◽

...

Keyword(s):

Smooth Muscle ◽

Guinea Pig ◽

Nitrogen Dioxide ◽

Airway Smooth Muscle ◽

Muscle Response ◽

In Vitro Exposure

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Effects of Bronchodilators Combined With Oscillations on the Contracted Airway Smooth Muscle

Volume 2: Biomedical and Biotechnology Engineering ◽

10.1115/imece2010-38357 ◽

2010 ◽

Author(s):

M. Mathur ◽

A. M. Al-Jumaily ◽

G. Ijpma ◽

R. Alany

Keyword(s):

Smooth Muscle ◽

Side Effects ◽

Airway Smooth Muscle ◽

Muscle Relaxants ◽

Combined Effects ◽

In Vitro Experiments ◽

Current Asthma ◽

Cardiovascular Side Effects ◽

Muscle Tissues

Current asthma treatments using anti-inflammatory agents and airway smooth muscle (ASM) relaxants are expensive, variable in effectiveness and are associated with several cardiovascular side effects. Previous in vitro experiments conducted on ASM tissues suggest that oscillations applied to contracted muscle result in a reduction in the contractile ability of the tissue. This study focuses on investigating the combined effects of muscle relaxants (bronchodilators) and length oscillations on the dynamics of contracted ASM. Isolated porcine tracheal smooth muscle tissues are contracted using Acetylcholine. Isoproterenol (Iso), a β-agonist, is used as a bronchodilator to relax the contracted ASM. Our results suggest that the combined effect of Iso and breathing oscillations is noted to be greater than the added effects of Iso and breathing alone. It can be proposed that breathing oscillations aid the relaxation of ASM by Isoproterenol.

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Chloride channel blockade relaxes airway smooth muscle and potentiates relaxation by β-agonists

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00351.2013 ◽

2014 ◽

Vol 307 (3) ◽

pp. L273-L282 ◽

Cited By ~ 12

Author(s):

Jennifer Danielsson ◽

Peter Yim ◽

Alison Rinderspacher ◽

Xiao Wen Fu ◽

Yi Zhang ◽

...

Keyword(s):

Smooth Muscle ◽

Guinea Pig ◽

Airway Smooth Muscle ◽

Chloride Channel ◽

Chloride Channels ◽

Ex Vivo ◽

Maintenance Phase ◽

Channel Blockers ◽

Asthmatic Patients ◽

Inward Currents

Severe bronchospasm refractory to β-agonists continues to cause significant morbidity and mortality in asthmatic patients. We questioned whether chloride channels/transporters are novel targets for the relaxation of airway smooth muscle (ASM). We have screened a library of compounds, derivatives of anthranilic and indanyloxyacetic acid, that were originally developed to antagonize chloride channels in the kidney. We hypothesized that members of this library would be novel calcium-activated chloride channel blockers for the airway. The initial screen of this compound library identified 4 of 20 compounds that relaxed a tetraethylammonium chloride-induced contraction in guinea pig tracheal rings. The two most effective compounds, compounds 1 and 13, were further studied for their potential to either prevent the initiation of or relax the maintenance phase of an acetylcholine (ACh)-induced contraction or to potentiate β-agonist-mediated relaxation. Both relaxed an established ACh-induced contraction in human and guinea pig ex vivo ASM. In contrast, the prevention of an ACh-induced contraction required copretreatment with the sodium-potassium-chloride cotransporter blocker bumetanide. The combination of compound 13 and bumetanide also potentiated relaxation by the β-agonist isoproterenol in guinea pig tracheal rings. Compounds 1 and 13 hyperpolarized the plasma cell membrane of human ASM cells and blocked spontaneous transient inward currents, a measure of chloride currents in these cells. These functional and electrophysiological data suggest that modulating ASM chloride flux is a novel therapeutic target in asthma and other bronchoconstrictive diseases.

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Inhibition of β-adrenoceptor agonist relaxation of airway smooth muscle by Ca2+-activated K+ channel blockers

European Journal of Pharmacology ◽

10.1016/0014-2999(93)90817-2 ◽

1993 ◽

Vol 235 (1) ◽

pp. 37-43 ◽

Cited By ~ 42

Author(s):

Jiao-Cheng Huang ◽

Maria L. Garcia ◽

John P. Reuben ◽

Gregory J. Kacsorowski

Keyword(s):

Smooth Muscle ◽

Airway Smooth Muscle ◽

K Channel ◽

Channel Blockers ◽

Adrenoceptor Agonist

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PPARγLigands Regulate Noncontractile and Contractile Functions of Airway Smooth Muscle: Implications for Asthma Therapy

PPAR Research ◽

10.1155/2012/809164 ◽

2012 ◽

Vol 2012 ◽

pp. 1-13 ◽

Cited By ~ 12

Author(s):

Chantal Donovan ◽

Xiahui Tan ◽

Jane Elizabeth Bourke

Keyword(s):

Smooth Muscle ◽

Airway Smooth Muscle ◽

Allergen Challenge ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Inflammatory Cytokine Production ◽

Novel Approach ◽

Independent Mechanism ◽

Adrenoceptor Agonists

In asthma, the increase in airway smooth muscle (ASM) can contribute to inflammation, airway wall remodeling and airway hyperresponsiveness (AHR). Targetting peroxisome proliferator-activated receptorγ(PPARγ), a receptor upregulated in ASM in asthmatic airways, may provide a novel approach to regulate these contributions. This review summarises experimental evidence that PPARγligands, such as rosiglitazone (RGZ) and pioglitazone (PGZ), inhibit proliferation and inflammatory cytokine production from ASMin vitro. In addition, inhaled administration of these ligands reduces inflammatory cell infiltration and airway remodelling in mouse models of allergen-induced airways disease. PPARγligands can also regulate ASM contractility, with acute treatment eliciting relaxation of mouse tracheain vitrothrough a PPARγ-independent mechanism. Chronic treatment can protect against the loss of bronchodilator sensitivity toβ2-adrenoceptor agonists and inhibit the development of AHR associated with exposure to nicotinein uteroor following allergen challenge. Of particular interest, a small clinical trial has shown that oral RGZ treatment improves lung function in smokers with asthma, a group that is generally unresponsive to conventional steroid treatment. These combined findings support further investigation of the potential for PPARγagonists to target the noncontractile and contractile functions of ASM to improve outcomes for patients with poorly controlled asthma.

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