Influence of β2-Adrenergic Receptor Genotype on Airway Function During Exercise in Healthy Adults

doi:10.1378/chest.129.3.762

Chest

Volume 129, Issue 3, March 2006, Pages 762-770

https://doi.org/10.1378/chest.129.3.762 Get rights and content

Background

In humans, β₂-adrenergic receptors (β₂ARs) influence airway tone. There are known functional polymorphisms of the β₂AR, such as substitution of glycine for arginine at codon 16. We sought to determine if this variation in genotype differentially influences airway function during exercise.

Methods

Healthy subjects without asthma who were either homozygous for Arg16 (n = 16; mean age, 29 ± 2 years [± SD]; mean maximum oxygen uptake [V̇o₂], 32 ± 2 mL/kg/min) or the Gly16 allele (n = 26; mean age, 30 ± 1 years; mean maximum V̇o₂, 33 ± 1 mL/kg/min) participated in the study. Baseline testing included spirometry and maximal symptom-limited exercise. On a separate day, an arterial cannula was placed to measure catecholamine levels. Subjects then performed exercise at two work levels (40% and 75% of peak work) for 9 min each and performed spirometry at 3-min intervals for assessment of airway function.

Results

There were no statistically significant differences between groups in maximum V̇o₂ or baseline spirometry (p > 0.05). With both light and heavy exercise, the groups had similar increases in the forced expiratory flow at 50% of vital capacity (FEF₅₀). FEF₅₀ increased by 14 ± 4% and 15 ± 3% in arginine and glycine groups, respectively, by end exercise (p > 0.05). During recovery (5 min and 10 min after), the Gly16 homozygotes demonstrated persistent bronchodilation (10 min after FEF₅₀ = + 7 ± 2% over pre-exercise) while the Arg16 subjects had a rapid return to baseline (10 min after FEF₅₀ = − 3 ± 3%, p = 0.007 between groups). No differences were observed in the catecholamine responses between genotypes, although the increase in epinephrine in the arginine group tended to be higher (p = 0.07).

Conclusions

These data suggest that the Arg16Gly polymorphism of the β₂AR does not influence airway function during short-duration low- and high-intensity exercise. However, during recovery, the Arg16 genotype is associated with a reduced bronchodilation, possibly due to increased catecholamine desensitization.

Section snippets

Subjects

The protocol was reviewed and approved by the Mayo Clinic Institutional Review Board, and all participants signed informed consent before entering the study. Age-, gender-, and activity-matched subjects were recruited from an existing pool of subjects who had previously been genotyped for the β₂AR as a part of a large study¹³ of the genetic associations with BP. Forty-two individuals who were homozygous for arginine (Arg16, n = 16) or glycine (Gly16, n = 26) at codon 16, and had no exclusion

Subject Characteristics

Subject characteristics did not differ significantly between genotype groups (Table 1). Baseline pulmonary function did not differ between the groups, although absolute lung volumes and flow rates tended to be slightly higher in the Gly16 subjects relative to the Arg16 subjects. Both groups of subjects demonstrated small but significant increases in FEF₅₀ and the average forced expiratory flow over the middle portion of the vital capacity (FEF_25–75) with the inhaled β-agonist (p < 0.05). No

Discussion

The focus of our study was to examine the influence of variation in the β₂AR gene at codon 16 on the airway responses to exercise in young, healthy adults. We found that the degree of bronchodilation with light- and heavy-intensity exercise was similar between the homozygous Arg16 and Gly16 subjects. However, during the recovery period, the maximal expiratory flow rates in the Arg16 subjects rapidly returned to or fell below baseline values, while the homozygous Gly16 subjects demonstrated a

ACKNOWLEDGMENT

We thank Kathy O’Malley and Angela Tarara for help with data collection, Renee Blumers for help with manuscript preparation, and the study participants for their efforts. We would also like to thank the staff of the GCRC for their assistance throughout this study, and Dr. Robert E. Hyatt for valuable discussions concerning the manuscript.

References (42)

GreenSA et al.
A polymorphism of the human β2-adrenergic receptor within the fourth transmembrane domain alters ligand binding and functional properties of the receptor
J Biol Chem
(1993)
GreenSA et al.
Implications of genetic variability of human β2-adrenergic receptor structure
Pulm Pharmacol
(1995)
TanS et al.
Association between β2-adrenoceptor polymorphism and susceptibility to bronchodilator desensitisation in moderately severe stable asthmatics
Lancet
(1997)
SkrabalF et al.
Inverse regulation of α-2 and β-2 adrenoceptors in salt-sensitive hypertension: a hypothesis
Life Sci
(1989)
JohnsonBD et al.
Ventilatory constraints during exercise in patients with chronic heart failure
Chest
(2000)
RouxE et al.
Muscarinic stimulation of airway smooth muscle cells
Gen Pharmacol
(1998)
CarstairsJR et al.
Autoradiographic localisation of β-adrenoceptors in human lung
Eur J Pharmacol
(1984)
HamidQA et al.
Localization of β2-adrenoceptor messenger RNA in human and rat lung using in situ hybridization: correlation with receptor autoradiography
Eur J Pharmacol
(1991)
DewarJC et al.
The glutamine 27 β2-adrenoceptor polymorphism is associated with elevated IgE levels in asthmatic families
J Allergy Clin Immunol
(1997)
DewarJC et al.
Association of the Gln 27 β2-adrenoceptor polymorphism and IgE variability in asthmatic families
Chest
(1997)

JoynerMJ et al.

β-Blockade reduces tidal volume during heavy exercise in trained and untrained men

J Appl Physiol

(1987)

WarrenJB et al.

Effect of adrenergic and vagal blockade on the normal human airway response to exercise

Clin Sci

(1984)

McGrawDW et al.

Transgenic overexpression of β(2)-adrenergic receptors in airway epithelial cells decreases bronchoconstriction

Am J Physiol Lung Cell Mol Physiol

(2000)

JohnsonBD et al.

Flow limitation and regulation of functional residual capacity during exercise in a physically active aging population

Am Rev Respir Dis

(1991)

JohnsonBD et al.

Demand vs. capacity in the aging pulmonary system

Exerc Sport Sci Rev

(1991)

JohnsonBD et al.

Mechanical constraints on exercise hyperpnea in endurance athletes

J Appl Physiol

(1992)

JohnsonBD et al.

Regulation of ventilatory capacity during exercise in asthmatics

J Appl Physiol

(1995)

CarstairsJR et al.

Autoradiographic visualization of β-adrenoceptor subtypes in human lung

Am Rev Respir Dis

(1985)

GiembyczMA et al.

Putative substrates for cyclic nucleotide-dependent protein kinases and the control of airway smooth muscle tone

J Auton Pharmacol

(1991)

GreenSA et al.

Amino-terminal polymorphisms of the human β2-adrenergic receptor impart distinct agonist-promoted regulatory properties

Biochemistry

(1994)

BrayMS et al.

Positional genomic analysis identifies the β(2)-adrenergic receptor gene as a susceptibility locus for human hypertension

Circulation

(2000)

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This review aims to systematically review and synthesize scientific evidence for the influence of air pollution exposure and outdoor exercise on health. We conducted a literature search in the PubMed, Cochrane, EMBASE, and Web of Science for articles that evaluated the combination effect of air pollution exposure and exercise on health. Questionnaires regarding exposure history, or studies examining indoor air pollution were excluded. Each included study needs to have clear exercise intervention plan. The pooled estimates of the combination effect of air pollution exposure and outdoor exercise on health were calculated in the meta-analysis. The quality of each included study was assessed and the quality of evidence for each outcome assessed in the meta-analysis was also measured. Twenty-five studies were identified. Six studies addressed ozone exposure, four diesel exhaust exposure, six traffic-related air pollution, ten particulate matter (PM) exposure. Only peak expiratory flow (effect size [ES] = −0.238, 95% confidence interval [CI] = −0.389, −0.088) was found to be significantly decreased after exercise intervention in a polluted environment in the meta-analysis. Seven studies reported exposure to air pollutant during exercise was associated with an increased risk of airway inflammation and decrements in pulmonary function. Six studies discovered that exposure of traffic pollution or high PM during exercise may contribute to changes in blood pressure, systemic conduit artery function and micro-vascular function. The combination effect of air pollution and exercise was found to be associated with the increased risk of potential health problems of cardiopulmonary function, immune function, and exercise performance.
Influence of polymorphisms of the beta-2 adrenergic receptor on the presence of exercise-induced bronchospasm in adolescents
2016, Revista Paulista de Pediatria
To determine the influence of polymorphisms of the beta-2 adrenergic receptor (ADRB2) in triggering exercise-induced bronchospasm (EIB) in adolescents.
The subjects were divided into two groups: present EIB (EIB+) (n=45) and absent EIB (EIB−) (n=115). The bronchial provocation test with exercise was performed with a protocol that consisted of walking/running for at least eight minutes at high intensity, i.e., >85% of maximum heart rate, considering EIB+ as a 10% decrease in forced expiratory volume in one second (FEV₁). The genotyping of the ADRB2 gene was performed by the Taqman method, using the Step One Plus system. Independent t-test, Mann–Whitney and Chi-square tests, as well as Spearman's correlation coefficient were used for the statistical analysis.
Age, body weight, height, FEV₁, FVC and FEV₁/FVC ratio were lower in the EIB+ group when compared to EIB− (p<0.05). There were no significant differences in the proportion of the allele at position 27 and Arg16Gly and Gln27Glu genotypes between the EIB+ and EIB− groups (p=0.26; p=0.97 and p=0.43, respectively). However, there was a trend toward statistical significance regarding the greater proportion of the Gly16 allele for the EIB+ when compared to the EIB− group (p=0.08).
The presence of polymorphisms associated with the Glu27 allele and Arg16Gly and Gln27Glu genotypes had no influence on EIB. However, the statistical trend toward greater frequency of the Gly16 allele in individuals with EIB+ can be considered evidence of the influence of polymorphisms of the ADBR2 gene on EIB in adolescents.
Determinar a influência dos polimorfismos dos receptores adrenérgicos beta 2 (ADRB2) no desencadeamento de broncoespasmo induzido pelo exercício (BIE) em adolescentes.
Os sujeitos foram divididos em dois grupos: BIE presente (BIE+) (n=45) e BIE ausente (BIE−) (n=115). O teste de broncoprovocação com exercício foi feito com protocolo que consistiu em caminhar/correr durante no mínimo oito minutos em intensidade superior a 85% da frequência cardíaca máxima, considerando como BIE presente uma queda de 10% do volume expiratório forçado no primeiro segundo (VEF₁). A genotipagem do gene ADRB2 foi feita pelo método Taqman por meio do aparelho Step One Plus. Para análise estatística usaram-se os testes t independente, U de Mann-Whitney, qui-quadrado e coeficiente de correlação de Spearman.
Idade, massa corporal, estatura, VEF₁, CVF e relação VEF₁/CVF foram menores no grupo BIE+ em comparação com o BIE− (p<0,05). Não houve diferenças significativas na proporção do alelo na posição 27 e dos genótipos Arg16Gly e Gln27Glu entre os grupos BIE+ e BIE− (p=0,26; p=0,97 e p=0,43, respectivamente). Entretanto, verificou-se uma tendência à significância estatística na maior proporção do alelo Gly16 para o grupo BIE+ comparado com o BIE− (p=0,08).
A presença de polimorfismos associados ao alelo Glu27 e os genótipos Arg16Gly e Gln27Glu não influenciam no BIE. Porém, a tendência estatística observada para uma maior frequência do alelo Gly16 nos indivíduos com a presença de BIE pode ser considerado indício da influência de polimorfismos no gene ADBR2 no BIE em adolescentes.
Effects of exercise intensity compared to albuterol in individuals with cystic fibrosis
2015, Respiratory Medicine
Citation Excerpt :
Additionally, DLNO, Q, and MEFV maneuvers were performed at the ten minute mark, and a blood sample was collected twelve minutes into exercise. The exercise protocol of fifteen minutes of submaximal exercise on a cycle ergometer was chosen as this duration would be similar to the administration time used with albuterol nebulization and would be sufficient to mediate an appropriate catecholamine response to induce bronchodilation [20]. The cycle ergometer was chosen as the mode of exercise to provide the most stable torso for the measurement of DLNO and Q.
Although exercise is a vital component of the therapy prescribed to individuals with cystic fibrosis (CF), it is not a priority due to a finite amount of treatment time and the view that exercise is not as beneficial as pharmacological treatments by many individuals with CF. We sought to compare the therapeutic benefits of exercise and their prescribed bronchodilator albuterol.
CF (n = 14) and healthy (n = 16) subjects completed three visits, a baseline screening with VO₂ max test and two treatment visits. On the two treatment visits, subjects completed spirometry and diffusing capacity of the lungs for nitric oxide (DLNO) maneuvers either at baseline, 60, and 110 min post-albuterol administration, or at baseline and the midway point of three separate 15 min exercise bouts at low, moderate and vigorous intensity (25, 50 and 65% of the maximum workload, respectively).
With moderate exercise the increase in DLNO was double (39 ± 8 vs 15 ± 6% change) and the level of bronchodilation similar (23% change) when compared to 110 min post-albuterol in individuals with CF. During exercise FVC became reduced (−309 ± 66 mL with moderate exercise) and the increase in FEV₁ was attenuated (103 ± 39 vs 236 ± 58 mL, exercise vs. albuterol) when compared with the response to albuterol in individuals with CF. Epinephrine (EPI) release increased 39, 72 and 144% change with low, moderate and vigorous intensity exercise respectively for individuals with CF, but this increase was blunted when compared to healthy subjects.
Our results suggest that moderate intensity exercise is the optimal intensity for individuals with CF, as low intensity exercise increases EPI less than 50% and vigorous intensity exercise is over taxing, such that airflow can be restricted. Although the duration of the beneficial effect is uncertain, exercise can promote greater improvements in gas diffusion and comparable bronchodilation when compared to albuterol.
Contribution of β-adrenergic receptors to exercise-induced bronchodilatation in healthy humans
2012, Respiratory Physiology and Neurobiology
Citation Excerpt :
Among the putative mechanisms are a decrease in vagal tone since the early stages of exercise (Warren et al., 1984a,b) and activation of β2-receptors by endogenous catecholamines (Joyner et al., 1987; McGraw et al., 2000; Snyder et al., 2006), as well as mechanical stretching (Agostoni et al., 2002; Pellegrino et al., 1999). Results from previous investigations on the potential role of the latter are, however, inconclusive with some negating any involvement of β2-adrenergic system (Warren et al., 1984a,b; Taylor et al., 1981) and others bringing opposite evidence (Warren et al., 1984b; Snyder et al., 2006; Joyner et al., 1987; McGraw et al., 2000). Among the possible reasons for these conflicting results are differences in the methods used for assessment of airway caliber.
Exercise in healthy subjects is usually associated with progressive bronchodilatation. Though the decrease in vagal tone is deemed to be the main underlying mechanism, activation of bronchial β₂-receptors may constitute an additional cause. To examine the contribution of β₂-adrenergic receptors to bronchodilatation during exercise in healthy humans, we studied 15 healthy male volunteers during maximum exercise test at control conditions and after a non-selective β-adrenergic blocker (carvedilol 12.5 mg twice a day until heart rate decreased at least by 10 beats/min) and inhaled β₂-agonist (albuterol 400 μg). Airway caliber was estimated from the partial flow at 40% of control forced vital capacity $({\dot{V}}_{part 40})$ and its changes during exercise from the slope of linear regression analysis of ${\dot{V}}_{part 40}$ values against the corresponding minute ventilation during maximal exercise until exhaustion. At control, ${\dot{V}}_{part 40}$ increased progressively and significantly with exercise. After albuterol, resting ${\dot{V}}_{part 40}$ was significantly larger than at control increased but did not further increase during exercise. After carvedilol, ${\dot{V}}_{part 40}$ was similar to control but its increase with exercise was significantly attenuated. These findings suggest that β₂-adrenergic system plays a major role in exercise-induced bronchodilation in healthy subjects.
Genetic variation of αENaC influences lung diffusion during exercise in humans
2011, Respiratory Physiology and Neurobiology
Citation Excerpt :
Exercise causes an increase in lymphatic drainage from the lungs. Maximal exercise results in an increase in epinephrine (an endogenous β2-adrenergic receptor agonist) up to 1000-fold that of rest (Snyder et al., 2006a). Because of exercise-induced increases in epinephrine, along with the SCNN1A genotype-related change in lung diffusion from rest to peak exercise, it is likely that baseline ENaC activity level and the response to activation of ENaC was the primary driving force for the differences observed in the present study.
Exercise, decompensated heart failure, and exposure to high altitude have been shown to cause symptoms of pulmonary edema in some, but not all, subjects, suggesting a genetic component to this response. Epithelial Na⁺ Channels (ENaC) regulate Na⁺ and fluid reabsorption in the alveolar airspace in the lung. An increase in number and/or activity of ENaC has been shown to increase lung fluid clearance. Previous work has demonstrated common functional genetic variants of the α-subunit of ENaC, including an A → T substitution at amino acid 663 (αA663T). We sought to determine the influence of the T663 variant of αENaC on lung diffusion at rest and at peak exercise in healthy humans. Thirty healthy subjects were recruited for study and grouped according to their SCNN1A genotype [n = 17 vs. 13, age = 25 ± 7 years vs. 30 ± 10 years, BMI = 23 ± 4 kg/m² vs. 25 ± 4 kg/m², ${\dot{V}}_{O_{2} peak} = 95 \pm 30 % pred . vs . 100 \pm 31 % pred.$ , mean ± SD, for AA (homozygous for αA663) vs. AT/TT groups (at least one αT663), respectively]. Measures of the diffusing capacity of the lungs for carbon monoxide (DL_CO), the diffusing capacity of the lungs for nitric oxide (DL_NO), alveolar volume (V_A), and alveolar-capillary membrane conductance (D_M) were taken at rest and at peak exercise. Subjects expressing the AA polymorphism of ENaC showed a significantly greater percent increase in DL_CO and DL_NO, and a significantly greater decrease in systemic vascular resistance from rest to peak exercise than those with the AT/TT variant (DL_CO = 51 ± 12% vs. 36 ± 17%, DL_NO = 51 ± 24% vs. 32 ± 25%, SVR = −67 ± 3 vs. −50 ± 8%, p < 0.05). The AA ENaC group also tended to have a greater percent increase in DL_CO/VA from rest to peak exercise, although this did not reach statistical significance (49 ± 26% vs. 33 ± 26%, p = 0.08). These results demonstrate that genetic variation of the α-subunit of ENaC at amino acid 663 influences lung diffusion at peak exercise in healthy humans, suggesting differences in alveolar Na⁺ and, therefore, fluid handling. These findings could be important in determining who may be susceptible to pulmonary edema in response to various clinical or environmental conditions.
Influence of Genetic variation of the β <inf>2</inf>-Adrenergic receptor on lung diffusion in patients with cystic fibrosis
2011, Pulmonary Pharmacology and Therapeutics
Cystic fibrosis (CF) is a disease that adversely affects the lung resulting in a reduction in lung diffusion. Stimulation of the β₂-adrenergic receptors mediates mucociliary clearance and bronchodilation. We sought to determine the influence of an inhaled β-agonist on the diffusing capacity of the lungs for carbon monoxide (DLCO), alveolar-capillary membrane conductance (D_M), pulmonary capillary blood volume (Vc), and peripheral oxygen saturation (SaO₂) in subjects with CF, when compared to matched healthy subjects, according to genetic variation of the β₂-adrenergic receptor (ADRB2).
To determine this we recruited 18 subjects with CF and 20 healthy subjects (age = 23 ± 7 vs. 24±4years; ht = 168 ± 8 vs. 174 ± 12 cm; wt = 64 ± 16 vs. 70 ± 13 kg; BMI = 23 ± 4 vs. 23±3 kg/m²; FEV₁ = 72 ± 27 vs. 92 ± 12%pred; VO_2peak = 45 ± 25 vs. 99 ± 24%pred, p < 0.05 for FEV₁ and VO_2peak, mean ± SD, for CF and healthy, respectively). The study involved measurement of DLCO, D_M, V_C and SaO₂ before and 30, 60, and 90 min following the administration of inhaled albuterol. Subjects were stratified according to genetic variation of ADRB2, Gln²⁷Gln vs. Glu²⁷Glu/Gln²⁷Glu.
Within the healthy group, there were no differences in DLCO, D_M, V_C, D_M/V_C at baseline or in response to albuterol according to genetic variation of the ADRB2 at amino acid 27. Within the CF group, the Glu²⁷Glu/Gln²⁷Glu group had higher D_M/V_C and SaO₂ when compared to the Gln²⁷Gln group at baseline (p < 0.05). Both genotype groups demonstrated a significant decline in V_C and an improvement in D_M/V_C and SaO₂ in response to albuterol. Subjects with the Glu²⁷ genotype experienced a greater improvement in D_M/V_C with albuterol when compared to subjects homozygous for Gln at amino acid 27.
These results suggest that there are differences in lung diffusion and peripheral SaO₂ according to genetic variation of the ADRB2 at position 27 which could play a potential role in dosing options or adjustments that may be required according to genotype.

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This work was supported by National Institutes of Health grants HL71478, HL63328, HL 54464, HL53330, and American Heart Association grant 56051Z.

The Mayo Clinic GCRC is supported by US Public Health Service grant M01-RR00585.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal.org/misc/reprints.shtml).

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Chest

Original Research: PHARMACOTHERAPYInfluence of β2-Adrenergic Receptor Genotype on Airway Function During Exercise in Healthy Adults

Background

Methods

Results

Conclusions

Section snippets

Subjects

Subject Characteristics

Discussion

ACKNOWLEDGMENT

J Biol Chem

Pulm Pharmacol

Lancet

Life Sci

Chest

Gen Pharmacol

Eur J Pharmacol

Eur J Pharmacol

J Allergy Clin Immunol

Chest

β-Blockade reduces tidal volume during heavy exercise in trained and untrained men

J Appl Physiol

Effect of adrenergic and vagal blockade on the normal human airway response to exercise

Clin Sci

Transgenic overexpression of β(2)-adrenergic receptors in airway epithelial cells decreases bronchoconstriction

Am J Physiol Lung Cell Mol Physiol

Flow limitation and regulation of functional residual capacity during exercise in a physically active aging population

Am Rev Respir Dis

Demand vs. capacity in the aging pulmonary system

Exerc Sport Sci Rev

Mechanical constraints on exercise hyperpnea in endurance athletes

J Appl Physiol

Regulation of ventilatory capacity during exercise in asthmatics

J Appl Physiol

Autoradiographic visualization of β-adrenoceptor subtypes in human lung

Am Rev Respir Dis

Putative substrates for cyclic nucleotide-dependent protein kinases and the control of airway smooth muscle tone

J Auton Pharmacol

Amino-terminal polymorphisms of the human β2-adrenergic receptor impart distinct agonist-promoted regulatory properties

Biochemistry

Positional genomic analysis identifies the β(2)-adrenergic receptor gene as a susceptibility locus for human hypertension

Circulation

Original Research: PHARMACOTHERAPY
Influence of β₂-Adrenergic Receptor Genotype on Airway Function During Exercise in Healthy Adults