Muscarinic control of airway function

doi:10.1016/S0024-3205(97)00048-9

Life Sciences

Volume 60, Issues 13–14, 21 February 1997, Pages 1061-1068

https://doi.org/10.1016/S0024-3205(97)00048-9 Get rights and content

Abstract

Muscarinic M₁, M₂, and M₃ receptor subtypes have been shown to be involved in the pre- and postjunctional control of airway diameter of various species, including man. In a guinea pig model of allergic asthma, the prejunctional M₂ receptor was shown to become dysfunctional already during the early allergic reaction, thereby contributing to exaggerated vagal reflex activity and airway hyperreactivity. Moreover, a deficiency of endogenous nitric oxide was observed after allergen provocation, which may also contribute to an enhanced postjunctional M₃ receptor-mediated cholinergic response. Both in human and in animal airway preparations it was shown that enhanced cholinergic contractions are relatively resistent to β-adrenoceptor-mediated relaxation. The reduced β-adrenoceptor function may primarily be due to transductional cross-talk between PI metabolism and adenylyl cyclase, including protein kinase C-induced uncoupling of the β-adrenoceptor from the effector system. Cross-talk between postjunctional M₂ receptor-mediated inhibition and β-adrenoceptor-induced activation of adenylyl cyclase appears to be of minor functional importance, but could be enhanced in allergic asthma due to increased expression of the inhibitory G protein as induced by cytokines.

References (40)

R.E.J. ten Berge et al.
Eur. J. Pharmacol.
(1993)
H. Kilbinger et al.
Life Sci.
(1995)
A.D. Fryer et al.
Life Sci.
(1993)
R.E. Santing et al.
J. Allergy Clin. Immunol.
(1994)
R.E.J. ten Berge et al.
Eur. J. Pharmacol.
(1996)
G.J. Gleich et al.
J. Allergy Clin. Immunol.
(1988)
H. Meurs et al.
Eur. J. Pharmacol.
(1988)
B.H. Hoiting et al.
Eur. J. Pharmacol.
(1995)
R.G.M. van Amsterdam et al.
Eur. J. Pharmacol.
(1989)
A.F. Roffel et al.
Eur. J Pharmacol.
(1993)

N. Watson et al.

Eur. J. Pharmacol.

(1995)

R.E.J. ten Berge et al.

Naunyn-Schmiedeberg's Arch. Pharmacol.

(1995)

A.F. Roffel et al.

A.D. Fryer et al.

Br. J. Pharmacol.

(1984)

H. Kilbinger et al.

Br. J. Pharmacol.

(1991)

Z.-J. Yang et al.

Can. J. Physiol. Pharmacol.

(1991)

P.A. Minette et al.

J. Appl. Physiol.

(1988)

N. Watson et al.

Br. J. Pharmacol.

(1992)

R.E.J. ten Berge et al.

Am. J. Respir. Crit. Care Med.

(1996)

P.A.H. Minette et al.

J. Appl. Physiol.

(1989)

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The effect of tiotropium in combination with olodaterol on house dust mite-induced allergic airway disease
2017, Pulmonary Pharmacology and Therapeutics
Citation Excerpt :
Muscarinic receptor signaling in the airways is primarily induced via the parasympathetic neurotransmitter acetylcholine released by both neuronal and non-neuronal cells including lung structural and inflammatory cells [7]. Signaling induces bronchoconstriction and mucus production by acting on smooth muscles and mucus-secreting cells in the central airways [8–11]. Blocking the receptor using therapeutic muscarinic receptor antagonists results in smooth muscle relaxation and reduced mucus production [12].
One of the major goals of asthma therapy is to maintain asthma control and prevent acute exacerbations. Long-acting bronchodilators are regularly used for the treatment of asthma patients and in clinical studies the anti-cholinergic tiotropium has recently been shown to reduce exacerbations in patients with asthma. So far it is unclear how tiotropium exerts this effect. For this purpose, we designed an allergen-driven rechallenge model of allergic airway inflammation in mice, to assess the effectiveness of tiotropium and the long-acting β-2 adrenoceptor agonist olodaterol on allergen-induced exacerbations of airway disease.
Female C57BL/6J mice were sensitized intranasally (i.n.) with 1 μg of house dust mite (HDM) extract followed by a challenge regime (5 consecutive days 10 μg HDM extract i.n.) after one week. Mice were exposed to a secondary challenge five weeks after sensitization and were treated i.n. with different concentrations of tiotropium or olodaterol (1, 10 and 100 μg/kg) or a combination thereof (10 μg/kg each) prior to and during the secondary challenge period. Three days after the last challenge, bronchoalveolar lavage (BAL) fluid and lung tissue were collected for flow cytometry and histologic analysis, respectively.
Secondary challenge with HDM extract strongly induced allergic airway disease reflected by inflammatory cell infiltration and goblet cell metaplasia. Treatment with tiotropium, but not with olodaterol reduced tissue inflammation and goblet cell metaplasia in a dose-dependent manner. The combination of tiotropium and olodaterol was more effective in significantly reducing tissue inflammation compared to tiotropium treatment alone, and also led to a decrease in BAL cell counts.
These data suggest that in a model of relapsing allergic airway disease tiotropium directly prevents exacerbations by reducing inflammation and mucus production in the airways. In addition, the combination of tiotropium and olodaterol exerts synergistic effects.
The impact of bilateral vagotomy on the physostigmine-induced airway constriction in ferrets
2017, Respiratory Physiology and Neurobiology
Vagal innervations have a great role in the respiratory function and are the main route of signal transmission from respiratory neural centers into the trachea and others conducting airways.
We have investigated the role of central mechanisms related to vagal neural pathways and the cholinergic outflow in tracheobronchial smooth muscle tone and lung mechanics parameters.
Parameters of lung mechanics such as lung resistance (RL), dynamic compliance (Cdyn) and pressure in bypassed tracheal segment (Ptseg) were measured before and after vagotomy and asphyxia test. Before vagotomy (BV), the control measurements were obtained and physostigmine was administered systemically, in increasing dose 10, 40 and 100 μg/kg body weight (bw) with 15 min interval between doses. After vagotomy (AV), administration of physostigmine with the same doses as BV has been done and the asphyxia challenge was conducted as per study protocol. The values of Ptseg and RL after physostigmine administration, BV vs. AV, respectively, at maximal dose of 100 μg/kg bw were 32.5 ± 3.3 cm H₂O, and 10.6 ± 1.5 cm H₂O (p < 0.0001); 0.16 ± 0.04 cm H₂O/mL/s, and 0.067 ± 0.006 cm H₂O/mL/s AV (P < 0.05). The Cydn values were affected after physostigmine administration only at the lowest dose of 10 μg/kg bw, and BV was 0.75 ± 0.05 mL/cm H₂O vs. 0.53 ± 0.04 mL/cm H₂O AV (P < 0.004).
Cholinergic outflow produced increases in tracheal tone, lung resistance and a decrease in dynamic compliance before, but not after vagotomy. Our results show the high impact of central neuronal mechanism in parameters of lung mechanics and respiration.
This study indicates that vagal nerves have a crucial role, in the transmission of impulses initiated from central nervous system, in regulating the respiration by contraction or relaxation of airway smooth muscle tone.
Bronchodilator activity of the selective muscarinic antagonist revatropate in horses with heaves
2013, Veterinary Journal
Citation Excerpt :
Consequently, inhalation therapy with muscarinic antagonists such as ipratropium has proven efficacy in attenuating airway obstruction in cases of heaves (Hoffman et al., 1993; Robinson et al., 1993; Duvivier et al., 1997). Revatropate offers potential advantages over non-specific antimuscarinic agents such as ipratropium, since it has significantly greater selectivity for the M3 and M1 muscarinic receptors on airway smooth muscle which mediate bronchoconstriction (Zaagsma et al., 1997) than for M2 receptors on cardiac muscle, thereby reducing undesirable cardiac effects such as tachycardia (Alabaster, 1997). Furthermore, unlike ipratropium, revatropate does not block the presynaptic inhibitory M2 receptors which may potentiate bronchoconstriction (Alabaster, 1997).
Bronchodilators are frequently used to attenuate airway obstruction in equine heaves (or recurrent airway obstruction). This study evaluated the selective (M₃ and M₁) muscarinic antagonist revatropate, which offers potential advantages over non-specific antimuscarinic agents such as ipratropium. Protocol 1 assessed the response to inhaled revatropate (1, 2 and 7 mg) using a blinded, negative (inhaled saline) and positive (inhaled ipratropium bromide; 0.3, 0.7 and 2 mg) controlled, dose escalation study, with six heaves horses. The lowest doses of revatropate and ipratropium induced a rapid (within 1 h) and significant improvement in airway function. The highest doses of both drugs had no significant effect on gastrointestinal sound score or iris function, but resulted in tacky mucous membranes and reduced gastrointestinal sound score in some horses.
In Protocol 2, a cross-over design comparing the duration of action of inhaled revatropate (1 mg), ipratropium (0.3 mg) and saline, some indices of airway function were improved for between 5 and 6 h after revatropate administration, and for between 6 and 24 h after ipratropium administration. Inhaled revatropate and ipratropium had similar effects on airway function, with no significant difference between their efficacies. Importantly, however, only revatropate significantly improved clinical scores of breathing effort, improving combined clinical score at the 1 h time point and abdominal score at the 1–3 h time points. No significant adverse events were observed in Protocol 2, although some horses had reduced gastrointestinal sound scores. Inhaled revatropate is therefore a safe and effective bronchodilator for treating airway obstruction in heaves.
Regulation of Lower Airway Function
2011, Fetal and Neonatal Physiology E-Book, Fourth Edition
Changes in muscarinic cholinergic receptor expression in human peripheral blood lymphocytes in allergic rhinitis patients
2008, Pulmonary Pharmacology and Therapeutics
Citation Excerpt :
Peripheral blood lymphocytes (PBLs) express the acetylcholine biosynthetic and catabolic enzymes [20] as well as M2, M3, M4 and M5 receptor subtypes [21,22]. A relationship between changes of lymphocyte cholinergic markers and central and peripheral cholinergic dysfunction has been suggested [23–31]. Moreover, increased lymphocyte muscarinic receptor expression has also been found in asthma patients with different degree of bronchial hyperreactivity documented by MIC hyperresponsiveness [32,33].
Parasympathetic nerves provide the dominant autonomic innervation of the upper and lower airways. They release acetylcholine that, activating post-junctional muscarinic receptors, causes bronchoconstriction, mucous secretion and vasodilation. Dysfunction of the upper and lower airways frequently coexist, and they appear to share key elements of pathogenesis.
The present study has assessed the expression and pattern of cholinergic muscarinic receptor subtypes in peripheral blood lymphocytes harvested from allergic rhinitis patients with different degree of bronchial hyperresponsiveness detected by methacholine challenge test.
Radioligand binding assay for determining the density of muscarinic cholinergic receptor subtypes; immunoblot analysis for assessing the characteristic of muscarinic cholinergic receptor subtype protein and immunocytochemical techniques for investigating the cellular localization of receptors.
An increased expression of M2 and M5 receptor proteins was observed in peripheral blood lymphocytes of allergic rhinitis patients in comparison with healthy control individuals. M3 receptor subtype decreased in allergic rhinitis patients with normal or mild responses to methacholine. A trend versus a return to normal value was found in moderate and severe responders. No changes of the M4 receptor subtype were found.
Increase in M2 receptor expression correlated with disease severity and bronchial hyperreactivity. Changes in muscarinic cholinergic receptor expression in allergic rhinitis underline a role of cholinergic system of immune cells in allergic airway disease.
Studies addressed to rhinitis and asthma have identified many similarities. Our results indicate that changes in peripheral blood lymphocyte muscarinic receptor expression may reflect the cholinergic involvement into allergic airway diseases.
Altered ion transport and responsiveness to methacholine and hyperosmolarity in air interface-cultured guinea-pig tracheal epithelium
2007, Journal of Pharmacological and Toxicological Methods
Challenge of guinea-pig tracheal epithelium with hyperosmolar solution alters ion transport and evokes the release of epithelium-derived relaxing factor (EpDRF). Cultured tracheal epithelial cells (CE) offer the potential to examine biochemical pathways related to EpDRF release, but whether the bioelectric properties and responses of fresh, adherent epithelial cells (FE) are modeled by CE has not been established. Methods: Tracheal epithelial cells grown in air-interface culture and fresh tracheal segments were mounted in Ussing chambers to determine short circuit current (I_sc) and transepithelial resistance (R_t) and to compare responses to transport inhibitors, methacholine and hyperosmolarity. Results: Significant differences in basal I_sc and R_t between FE and CE were observed (I_sc, 41.3 ± 3.5 and 8.5 ± 0.8 μA/cm², P < 0.05; R_t, 106 ± 7 and 422 ± 4 Ω cm², P < 0.05; respectively); basal spontaneous potential difference values were not different (4.2 ± 0.3 and 3.4 ± 0.3 mV, respectively). Amiloride (mucosal, 3 × 10^− 5 M), bumetanide (basolateral, 10^− 5 M) and ouabain (basolateral, 10^− 5 M) reduced I_sc equally in FE and CE. In contrast, NPPB (10^− 5 M) in the presence of amiloride had a differential effect, decreasing I_sc by 11% in FE and 71% in CE (P < 0.05). Iberiotoxin (basolateral, 10^− 7 M) was without effect in either preparation. In FE, serosal methacholine (3 × 10^− 5 M) elicited an NPPB-insensitive monotonic increase in I_sc, but in CE caused a large, transient, NPPB-inhibitable increase which was followed by an NPPB-resistant plateau. Addition of apical d-mannitol (0.3–267 mosM) to increase osmolarity decreased I_sc in FE, whereas in CE d-mannitol initially increased (0.3–84.3 mosM) and then decreased (84.3–267 mosM) I_sc. Discussion: Cell culture causes substantial changes in the bioelectric and pharmacological properties of respiratory epithelium. Caution should be exercised when using CE as a substitute for FE in studies of ion transport- and cell volume-dependent processes.

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Muscarinic control of airway function

Abstract

Eur. J. Pharmacol.

Life Sci.

Life Sci.

J. Allergy Clin. Immunol.

Eur. J. Pharmacol.

J. Allergy Clin. Immunol.

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Eur. J Pharmacol.

Eur. J. Pharmacol.

Naunyn-Schmiedeberg's Arch. Pharmacol.

Br. J. Pharmacol.

Br. J. Pharmacol.

Can. J. Physiol. Pharmacol.

J. Appl. Physiol.

Br. J. Pharmacol.

Am. J. Respir. Crit. Care Med.

J. Appl. Physiol.