Bronchial responsiveness to beta‐adrenergic stimulation and enhanced beta‐blockade in asthma

Boskabady, M.H.; Snashall, P. D.

doi:10.1046/j.1440-1843.2000.00236.x

Cited by 25 publications

(36 citation statements)

References 25 publications

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“…When administered acutely, they increased AR, whereas chronically, they significantly decreased the maximal constrictor response to methacholine. Whereas the acute effects of nadolol and carvedilol are in line with the reported effects of single-dose administration of nonselective ␤-blockers such as propranolol or timolol to asthmatic subjects (33) and various animal models (34)(35)(36)(37), the long-term effects of these drugs on airway responsiveness represent a major finding that could have therapeutic implications. It is noteworthy that a similar timedependent opposite effect has also been observed with certain ␤-blockers in the treatment of CHF.…”

Section: Effect Of ␤-Ar Ligands On Airway Responsiveness To Methacholmentioning

confidence: 66%

Effects of acute and chronic administration of β-adrenoceptor ligands on airway function in a murine model of asthma

Callaerts-Végh

Evans

Dudekula

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

144

143

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The clinical effects of treatment with ␤-adrenoceptor (␤-AR) agonists and antagonists in heart failure vary with duration of therapy, as do the effects of ␤-AR agonists in asthma. Therefore, we hypothesized that chronic effects of ''␤-blockers'' in asthma may differ from those observed acutely. We tested this hypothesis in an antigen (ovalbumin)-driven murine model of asthma. Airway resistance responses (R aw) to the muscarinic agonist methacholine were measured by using the forced oscillation technique. In comparison with nontreated asthmatic mice, we observed that: (i) The ␤-AR antagonists nadolol or carvedilol, given as a single i.v. injection (acute treatment) 15 min before methacholine, increased methacholine-elicited peak R aw values by 33.7% and 67.7% (P < 0.05), respectively; when either drug was administered for 28 days (chronic treatment), the peak R aw values were decreased by 43% (P < 0.05) and 22.9% (P < 0.05), respectively. (ii) Chronic treatment with nadolol or carvedilol significantly increased ␤-AR densities in lung membranes by 719% and 828%, respectively. (iii) Alprenolol, a ␤-blocker with partial agonist properties at ␤-ARs, behaved as a ␤-AR agonist, and acutely reduced peak Raw value by 75.7% (P < 0.05); chronically, it did not alter Raw. (iv) Salbutamol, a ␤-AR partial agonist, acutely decreased peak R aw by 41.1%; chronically, it did not alter Raw. (v) None of the ␤-blockers produced significant changes in eosinophil number recovered in bronchoalveolar lavage. These results suggest that ␤-AR agonists and ␤-blockers with inverse agonist properties may exert reciprocating effects on cellular signaling dependent on duration of administration.␤-blockers ͉ sympathomimetics ͉ airway resistance ͉ inverse agonist

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Section: Effect Of ␤-Ar Ligands On Airway Responsiveness To Methacholmentioning

confidence: 66%

Effects of acute and chronic administration of β-adrenoceptor ligands on airway function in a murine model of asthma

Callaerts-Végh

Evans

Dudekula

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

144

143

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“…Eosinophils in BAL may demonstrate the importance of asthma as one of the main pulmonary complications of chemical warfare [7]. The cause of reversibility in airway obstruction may be due to development of sulfur mustard gas-induced AHR, as AHR to brochodilators (isoprenaline and salbutamol) in asthmatic patients and its relationship to responsiveness to bronchoconstrictors (methacholine and histamine) were demonstrated previously [23, 24]. …”

Section: Discussionmentioning

confidence: 94%

Airway Hyperresponsiveness to Methacholine in Chemical Warfare Victims

Mirsadraee

Attaran²,

Boskabady³

et al. 2005

Respiration

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Background: The lung is one of the most exposable organs to chemical warfare agents such as sulfur mustard gas. Pulmonary complications as a result of this gas range from severe bronchial stenosis to mild or no symptoms. Airway hyperresponsiveness (AHR) which is usually assessed as response to inhaled methacholine is the most characteristic feature of asthma. AHR is reported in chronic obstructive pulmonary disease patients and smokers, and may also show in chemical warfare victims. However, there are little reports regarding AHR in chemical warfare victims. Objective: Therefore, in this study, airway responsiveness to methacholine in victims of chemical warfare was examined. Methods: The threshold concentrations of inhaled methacholine required for a 20% change in forced expiratory flow in 1 s (FEV₁; PC₂₀) or a 35% change in specific airway conductance (PC₃₅) were measured in 15 chemical war victims and 15 normal control subjects. Results: In 10 out of 15 chemical warfare victims (two thirds), PC₂₀ and PC₃₅ methacholine could be measured and subjects were called responders. AHR to methacholine in responder chemical war victims (PC₂₀ = 0.41 and PC₃₅ = 0.82 g/l) was significantly lower than in normal subjects (PC₂₀ = 5.69 and PC₃₅ = 4.60 g/l, p < 0.001 for both cases). There was a significant correlation between FEV₁ and PC₂₀ methacholine (r = 0.688, p < 0.001). The correlations between PC₂₀ and PC₃₅ were statistically significant as well (r = 0.856, p < 0.001). Conclusion: Results showed increased airway responsiveness of most chemical warfare victims to methacholine which correlated with the FEV₁ value and which may be related to chronic airway inflammation or irreversible airway changes.

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“…These studies suggest that signaling via constitutively active, unligated b-adrenoceptors contributes significantly to mucous metaplasia. b-blockers are currently contraindicated in asthma because their acute administration may cause increased airway resistance (83,84), but a small, open-label pilot study in subjects with mild asthma showed that escalating doses of nadolol were well tolerated and treatment resulted in a dose-dependent improvement in airway hyperresponsiveness, as assessed by PC 20 to methacholine (85).…”

Section: Anti-inflammatory Therapiesmentioning

confidence: 99%

Advances in Mucous Cell Metaplasia

Curran

Cohn

2010

Am J Respir Cell Mol Biol

164

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Mucous cell metaplasia is induced in response to harmful insults and provides front-line protection to clear the airway of toxic substances and cellular debris. In chronic airway diseases mucous metaplasia persists and results in airway obstruction and contributes significantly to morbidity and mortality. Mucus hypersecretion involves increased expression of mucin genes, and increased mucin production and release. The past decade has seen significant advances in our understanding of the molecular mechanisms by which these events occur. Inflammation stimulates epidermal growth factor receptor activation and IL-13 to induce both Clara and ciliated cells to transition into goblet cells through the coordinated actions of FoxA2, TTF-1, SPDEF, and GABA A R. Ultimately, these steps lead to up-regulation of MUC5AC expression, and increased mucin in goblet cell granules that fuse to the plasma membrane through actions of MARCKS, SNAREs, and Munc proteins. Blockade of mucus in exacerbations of asthma and chronic obstructive pulmonary disease may affect morbidity. Development of new therapies to target mucus production and secretion are now possible given the advances in our understanding of molecular mechanisms of mucous metaplasia. We now have a greater incentive to focus on inhibition of mucus as a therapy for chronic airway diseases.

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Bronchial responsiveness to beta‐adrenergic stimulation and enhanced beta‐blockade in asthma

Cited by 25 publications

References 25 publications

Effects of acute and chronic administration of β-adrenoceptor ligands on airway function in a murine model of asthma

Effects of acute and chronic administration of β-adrenoceptor ligands on airway function in a murine model of asthma

Airway Hyperresponsiveness to Methacholine in Chemical Warfare Victims

Advances in Mucous Cell Metaplasia

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