β&lt;sub&gt;2&lt;/sub&gt;-Agonists and Bronchial Hyperresponsiveness

Page, Clive; Spina, Domenico

doi:10.1385/criai:31:2:143

Cited by 16 publications

(13 citation statements)

References 184 publications

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“…Steroids have shown in experimental in vitro and in vivo studies to reverse functional desensitisation of b 2 -AR [4,23,24], increase receptor expression and density, and enhance expression of G s a, producing a dose-dependent increase in cyclic adenosine monophosphate levels [25,26]. However, in humans, loss of bronchoprotection from regularly administered b 2 -agonists seems to reverse only with acute high doses of ICS [27,28] and it is not clear that this happens with chronic use of ICS at low or medium doses [29][30][31]. Recent findings suggest that the mechanism by which ICS plus LABA therapy exerts its synergistic beneficial effects is through an increased antiinflammatory activity and an attenuation of airway remodelling [32].…”

Section: Discussionmentioning

confidence: 99%

ADRB2 Gly16Arg polymorphism, asthma control and lung function decline

Rebordosa¹,

Kogevinas

Guerra

et al. 2011

European Respiratory Journal

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Arg/Arg homozygotes for the Gly16Arg polymorphism in the b 2 -adrenoreceptor gene (ADRB2) have a reduced response to short-acting b 2 -agonists but no effect has been associated with long-acting b 2 -agonists (LABAs).We selected 604 subjects with current asthma from the European Community Respiratory Health Study to evaluate whether asthma control and lung function decline were associated with Gly16Arg polymorphism, and to test whether LABA or inhaled corticosteroid (ICS) use modified these effects.There was an increased risk of noncontrolled asthma (OR 1.33, 95% CI 1.01-1.75; p50.046) for each Arg allele. Among nonusers of ICS, the odds ratio of noncontrolled asthma among Arg/Arg versus Gly/Gly subjects was 2.73 (95% CI 1.28-5.82; p50.009). No increased risk of noncontrolled asthma associated with the Arg allele was observed among ICS and/or LABA users. For each Arg allele, a mean¡SE decrease in decline in forced expiratory volume in 1 s of 7.7¡2.5 mL?yr -1 was found (p-value for trend 0.003), irrespective of ICS or LABA use. Arg/Arg subjects had an increased risk of bronchial hyperresponsiveness (BHR) versus Gly/Gly subjects, with an odds ratio of 2.51 (95% CI 1.12-5.63; p50.025) if they did not use ICS. The Arg allele was associated with poorer asthma control, a steeper lung function decline and BHR. Absence of genotypic effects on asthma control among ICS users may be due to reversed b 2 -adrenoreceptor desensitisation.

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Section: Discussionmentioning

confidence: 99%

ADRB2 Gly16Arg polymorphism, asthma control and lung function decline

Rebordosa¹,

Kogevinas

Guerra

et al. 2011

European Respiratory Journal

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“…Similarly, a number of studies have shown that regular treatment with SABAs and LABAs is associated with a loss in bronchoprotection to direct and indirect acting stimuli [54,55 Regular treatment with salmeterol did not cause bronchodilator tolerance as assessed by improvement in forced expiratory volume in 1 s (FEV1) in response to this bronchodilator; however, there was a significant loss in bronchoprotection against methacholine challenge from 3.3 doubling doses on day 0, decreasing to 1 doubling dose after 8 weeks regular treatment [56], and a similar observation has been observed for formoterol [57]. This loss in bronchoprotection is also observed in studies that examined the ability of salbutamol to reverse acute bronchospasm in response to methacholine in individuals regularly receiving LABAs, in an attempt to replicate circumstances in which asthma patients might undergo an exacerbation of their asthma during maintenance LABAs, who require rescue medication.…”

Section: Loss Of Bronchoprotectionmentioning

confidence: 98%

Current and novel bronchodilators in respiratory disease

Spina

2014

Current Opinion in Pulmonary Medicine

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Novel long-acting β2-agonists (e.g. indacaterol, vilanterol, olodaterol and carmoterol) and muscarinic antagonists (e.g. tiotropium, aclidinium, glycopyrronium and umeclidinium bromide) document sustained bronchodilation and their combination provides additional benefits over monotherapy. Not surprisingly, inhaled long-acting β2-agonist and long-acting muscarinic antagonists remain the drugs of choice for maintenance bronchodilation. However, there is a continued interest in developing novel bronchodilators illustrated by the clinical effectiveness of long acting mixed PDE3/4 inhibitors, vasointestinal peptide adenylyl cyclase agonists and inverse agonists/biased agonists for the β2-adrenoceptor, and the identification of intracellular (e.g. Rho kinase, exchange proteins activated by cyclic AMP) and cell surface (e.g. TAS2R, natriuretic peptide receptor) targets.

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“…The ability of these therapies to inhibit AHR has in turn provided some explanation as to the mechanisms of direct AHR. Acutely, β 2 -agonists are powerful inhibitors of ASM contractility capable of decreasing AHR to direct stimuli (Page and Spina, 2006). β 2 -agonists protect against ASM contraction from direct stimuli by non-specific functional antagonism via β 2 receptor-induced ASM relaxation.…”

Section: Assessing Efficacy Of Asthma Pharmacotherapy Using Ahrmentioning

confidence: 99%

Airway Hyperresponsiveness in Asthma: Mechanisms, Clinical Significance, and Treatment

Brannan¹,

Lougheed²

2012

Front. Physio.

115

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Airway hyperresponsiveness (AHR) and airway inflammation are key pathophysiological features of asthma. Bronchial provocation tests (BPTs) are objective tests for AHR that are clinically useful to aid in the diagnosis of asthma in both adults and children. BPTs can be either “direct” or “indirect,” referring to the mechanism by which a stimulus mediates bronchoconstriction. Direct BPTs refer to the administration of pharmacological agonist (e.g., methacholine or histamine) that act on specific receptors on the airway smooth muscle. Airway inflammation and/or airway remodeling may be key determinants of the response to direct stimuli. Indirect BPTs are those in which the stimulus causes the release of mediators of bronchoconstriction from inflammatory cells (e.g., exercise, allergen, mannitol). Airway sensitivity to indirect stimuli is dependent upon the presence of inflammation (e.g., mast cells, eosinophils), which responds to treatment with inhaled corticosteroids (ICS). Thus, there is a stronger relationship between indices of steroid-sensitive inflammation (e.g., sputum eosinophils, fraction of exhaled nitric oxide) and airway sensitivity to indirect compared to direct stimuli. Regular treatment with ICS does not result in the complete inhibition of responsiveness to direct stimuli. AHR to indirect stimuli identifies individuals that are highly likely to have a clinical improvement with ICS therapy in association with an inhibition of airway sensitivity following weeks to months of treatment with ICS. To comprehend the clinical utility of direct or indirect stimuli in either diagnosis of asthma or monitoring of therapeutic intervention requires an understanding of the underlying pathophysiology of AHR and mechanisms of action of both stimuli.

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β<sub>2</sub>-Agonists and Bronchial Hyperresponsiveness

Cited by 16 publications

References 184 publications

ADRB2 Gly16Arg polymorphism, asthma control and lung function decline

ADRB2 Gly16Arg polymorphism, asthma control and lung function decline

Current and novel bronchodilators in respiratory disease

Airway Hyperresponsiveness in Asthma: Mechanisms, Clinical Significance, and Treatment

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