Category - Part 6
Influence of p2-Adrenergic Receptor Genotype on Airway Function During Exercise in Healthy Adults: Study Limitations
We only investigated the role of a single-nucleotide polymorphism (SNP) on physiologic function. Previous work by Drysdale and colleagues sequenced the entire P2AR in a large population of asthmatics. They subsequently grouped the SNPs according to haplotypes; and while no SNP was associated with response to a P-agonist, combinations of SNPs grouped according to haplotype pairs did predict P-agonist responsiveness. Thus, it is possible that grouping subjects according to P2AR haplotype may more accurately predict the airway changes during and after exercise. Other stud-ies have suggested that position 27 may also play a role in modulating receptor function. When we examined the influence of variation at position 27, the homozygous Gly16/Gln27 haplotype tended to have the largest changes in FEF50 during heavy exercise, followed by the Gly16Gly/Gln27Glu combination, the homozygous Arg16/Gln27 group, and finally the homozygous Gly16/Glu27 haplotype, suggesting that Gln at position 27 may be more catecholamine sensitive. However, none of the differences that were observed at 5 min and 10 min of recovery could be explained by position 27. Another limitation of this study was the small sample size in light of the inherent difficulties in identifying subtle changes in airway tone both during and in the recovery phase of exercise in healthy adults and the likely small influence of common polymorphisms of the P2AR on airway smooth-muscle function. http://buy-asthma-inhalers-online.com/advair-diskus-inhaler-fluticasone-salmeterol.html
Influence of p2-Adrenergic Receptor Genotype on Airway Function During Exercise in Healthy Adults: Conclusion
Interestingly, the difference between the Arg16 and Gly16 genotypes in FEF50 occurred during a time when catecholamines were rapidly returning to baseline after the airway P2ARs had been exposed to catecholamines for 10 to 15 min (exercise plus early cool down). This may suggest that significant in vivo desensitization takes between 9 min and 15 min to occur. Garovic et al infused a P-agonist (isoproterenol) at increasing concentrations and measured changes in forearm blood flow in Arg16 and Gly16 homozygotes. http://birthcontroltab.com/buy-alesse-online.html
They found that the Arg16 group had smaller increases in forearm blood flow but did not observe a significant difference between the groups until 6 to 12 min of infusion.
Although a difference in FEF50 between the groups was demonstrated during recovery from exercise, there were no significant differences between the groups in response to a single inhalation of a P-agonist. All subjects followed a standard protocol, which included prebronchodilator spirometry, inhalation of albuterol, followed by a 10 to 15-min rest prior to repeat spirometry. Albuterol is a long-acting P2-selective agonist that has been shown to lead to bronchodilation in a manner that is consistent with exercise-related catecholamine stimulation. The lack of difference between the groups with an inhaled P2-agonist may be due to a slightly shorter time period prior to repeat spirometry (vs exercise), or possibly it is due to different mechanisms of action related to the large endogenous and constant infusion of catecholamines with exercise presumably through the bronchiole circulation vs the effects of a single breath of an inhaled P-agonist.
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Influence of p2-Adrenergic Receptor Genotype on Airway Function During Exercise in Healthy Adults: Discussion
The coding region of the P2AR demonstrates multiple sites of polymorphic variation such as positions 16, 27, and 164. Positions 16 and 27 have been studied extensively both in vitro and in oioo. In vitro, the most impaired polymorphic receptor appears to be due to a threonine to isoleucine change at amino acid 164. However, the heterozygous condition at amino acid 164 occurs in < 5% of the normal population, and the homozygous Ile164 has not been observed in large samples from the general population. In the present study, we chose to examine the effects of exercise on airway function in the Arg16Gly polymorphism, since it is commonly found in the population and also appears to be functionally important. Due to linkage disequilibrium, all homozygous Arg16 subjects in the present study were also homozygous for glutamine at position 27, while position 27 varied (homozygous for glutamine or glutamate, or heterozygous) in the homozygous Gly16 subjects. http://asthma-inhalers-online.com/buy-generic-proventil-online.html
Influence of p2-Adrenergic Receptor Genotype on Airway Function During Exercise in Healthy Adults: Airway Responses to Exercise
The focus of our study was to examine the influence of variation in the P2AR 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 sustained elevation in FEF50 (over pre-exercise values).
A number of previous studies’’’ have demonstrated exercise-related bronchodilation in healthy adults. In the present study, we noted a small rise in FEF50 (3 to 6%) during light exercise with a tendency for the Gly16 subjects to have a greater response. This occurred at a time when catecholamine levels were essentially unchanged from baseline. Thus, it is unlikely that the observed changes with light exercise were due to stimulation of the P2AR unless there are noncatecholamine-mediated pathways that exist, such as a reported interaction between the muscarinic and the P2ARs. The fact that there were only small changes in FEF50 with light exercise suggests that release of vagal tone likely plays little role in the bronchodilation of exercise given this occurred at a time when vagal withdrawal should have been prominent.
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Influence of p2-Adrenergic Receptor Genotype on Airway Function During Exercise in Healthy Adults: Catecholamine Response to Exercise
Figure 1 shows the changes in arterial levels of epinephrine and norepinephrine during low- and high-intensity exercise as well as during recovery (expressed as the percentage change from rest). No significant differences were observed between groups, although the Arg16 subjects tended to have a greater increase in epinephrine than the Gly16 subjects (p = 0.07).
Small changes were observed in FEF50 with low-intensity exercise in each genotype group (3 to 6%; p = 0.002 from rest). Both groups demonstrated similar increases in bronchodilation during heavy exercise (averaging 14% and 15% for the homozygous Arg16 and Gly16 subjects, respectively, over the last 3 min of exercise; p < 0.001, from rest), and there were no statistically significant differences between the Arg16 and Gly16 groups in the degree of bronchodilation (Fig 2). During the recovery period, at 5 min and 10 min after exercise, both groups had a decrease in FEF50, but the FEF50 returned to baseline or below in 12 of 16 Arg16 subjects, while 20 of 26 Gly16 subjects had sustained, mild bronchodilation (p < 0.001).
Influence of p2-Adrenergic Receptor Genotype on Airway Function During Exercise in Healthy Adults: Subject Characteristics
The demographic data were examined using independent t tests with an a = 0.05. We used analysis of variance to examine differences in the primary outcome measure, FEF50 (SPSS; Chicago, IL). An analysis of covariance was also performed between the groups with epinephrine as the covariate and FEF50 as the dependent variable. Prior to beginning the study, and based on previous data from our laboratory on measures of FEF50 at rest and during exercise (and the changes observed with exercise), we estimated that we could detect a difference between genotype groups (homozygous Arg16 vs Gly16) for the percentage change from baseline of 3.5% with n = 16 and n = 26, respectively, for the groups with 85% power.
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Influence of p2-Adrenergic Receptor Genotype on Airway Function During Exercise in Healthy Adults: Data Collection
Cardiopulmonary Assessment During Exercise: Measurements of oxygen uptake (Vo2) and the elimination of carbon dioxide were measured continuously during the various exercise tests and stages using a metabolic cart (Medical Graphics; St. Paul, MN) interfaced with a mass spectrometer (Perkin Elmer; Wellesley, MA). This system has been validated against classic “bag” collection techniques, and stability is verified by regular testing at standard exercise intensities by laboratory personnel.
Catecholamines (epinephrine and norepinephrine) were assessed according to methods developed in the Mayo Clinic GCRC immunochemical core laboratory and the methods of Sealey. For our laboratory, intraassay coefficient of variations (CVs) are as follows: norepinephrine, 4.5% and 3.3% at 224 pg/mL and 429 pg/mL; and epinephrine, 12.2% and 3.6% at 13.8 pg/mL and 242 pg/mL, respectively. Interassay CVs are as follows: norepinephrine, 8.2% and 6.3% at 337 pg/mL and 533 pg/mL; and epinephrine, 8.5% and 6.3% at 179 pg/mL and 390 pg/mL, respectively. www.buy-asthma-inhalers-online.com