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Original Research: Asthma |

Acute Effect of an Inhaled Glucocorticosteroid on Albuterol-Induced Bronchodilation in Patients With Moderately Severe AsthmaMometasone, Airway Blood Flow, and Albuterol FREE TO VIEW

Eliana S. Mendes, MD; Lilian Cadet, RT; Johana Arana; Adam Wanner, MD, FCCP
Author and Funding Information

From the Division of Pulmonary, Critical Care and Sleep Medicine, University of Miami Miller School of Medicine, Miami, FL.

CORRESPONDENCE TO: Eliana S. Mendes, MD, Division of Pulmonary, Critical Care and Sleep Medicine, 1600 NW 10th Ave #7064-A, University of Miami Miller School of Medicine, Miami, FL 33136; e-mail: emendes@med.miami.edu


FUNDING/SUPPORT: This study was supported by an academic grant from Merck & Co, Inc.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2015;147(4):1037-1042. doi:10.1378/chest.14-1742
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Published online

BACKGROUND:  We have previously shown that in patients with asthma a single dose of an inhaled glucocorticosteroid (ICS) acutely potentiates inhaled albuterol-induced airway vascular smooth muscle relaxation through a nongenomic action. An effect on airway smooth muscle was not seen, presumably because the patients had normal lung function. The purpose of the present study was to conduct a similar study in patients with asthma with airflow obstruction to determine if an ICS could acutely also potentiate albuterol-induced airway smooth muscle relaxation in them.

METHODS:  In 15 adult patients with asthma (mean ± SE baseline FEV1, 62% ± 3%), the response to inhaled albuterol (180 μg) was assessed by determining the change in FEV1 (ΔFEV1) for airway smooth muscle and in airway blood flow (ΔQaw) for airway vascular smooth muscle measured 15 min after drug inhalation. Using a double-blind design, the patients inhaled a single dose of the ICS mometasone (400 μg) or placebo simultaneously with or 30 min before albuterol inhalation.

RESULTS:  After simultaneous drug administration, mean ΔFEV1 was 0.20 ± 0.05 L (10%) after placebo and 0.32 ± 0.04 L (19%) after mometasone (P < .05); mean ΔQaw was −2% after placebo and 30% after mometasone (P < .005). When mometasone or placebo was administered 30 min before albuterol, there was a lesser and insignificant difference in ΔFEV1 between the two treatments, whereas the difference in ΔQaw remained significant.

CONCLUSIONS:  This pilot study showed that in adult patients with asthma with airflow obstruction, a single standard dose of an ICS can acutely increase the FEV1 response to a standard dose of inhaled albuterol administered simultaneously. The associated potentiation of albuterol-induced vasodilation in the airway was of greater magnitude and retained when the ICS was administered 30 min before albuterol. The clinical significance of this observation will have to be established by a study involving a larger patient cohort.

TRIAL REGISTRY:  ClinicalTrials.gov; No.: NCT01210170; URL: www.clinicaltrials.gov

Figures in this Article

Glucocorticosteroids inhibit the disposal of organic cations by blocking organic cation transporters expressed by nonneuronal cells through a pharmacologic nongenomic action, thereby interfering with the inactivation of the organic cations by intracellular enzymes.13 We have shown in human airway vascular smooth muscle cells that the glucocorticosteroid action on organic cation uptake occurs within minutes, does not involve gene transcription or protein synthesis, is not mediated through classic steroid receptors, and is cell membrane linked.3,4

This steroid effect is likely to acutely increase the concentration of organic cations including α- and β-adrenergic agonists at adrenergic receptor sites on smooth muscle. The airway contains two types of smooth muscle: airway smooth muscle and airway vascular smooth muscle. Therefore, inhaled glucocorticosteroids (ICSs), owing to their inhibitory action on organic cation transporters, could be expected to decrease the local disposal of inhaled β2-adrenergic agonists and locally released norepinephrine, the latter resulting in vasoconstriction. Both ICS effects would potentiate inhaled β2-adrenergic agonist-induced bronchodilation by interfering with the drug’s local disposal and vascular clearance.

This nongenomic glucocorticosteroid effect has been confirmed in vivo by showing that high-dose ICSs cause a dose-dependent decrease in airway blood flow (Qaw) that can be blocked with an α1-adrenergic antagonist5,6 and by showing that the airway vascular smooth muscle response to inhaled albuterol is potentiated by pretreatment with a single low dose of an ICS that by itself does not cause vasoconstriction.7 An effect of the ICS on albuterol-induced bronchodilation was not seen, possibly because steroid-naive patients with mild asthma were included in the study; baseline airway caliber was in or near the normal range, presumably negating the possibility of detecting significant bronchodilation. Thus, the previous study could not be satisfactorily interpreted with respect to its clinical relevance (ie, acute potentiation of β2-adrenergic agonist-induced bronchodilation).

In the present proposal we, therefore, wished to extend the previous study with a more informative protocol by administering a single standard dose of mometasone simultaneously with or 30 min before inhalation of a standard dose of albuterol in subjects with moderate persistent asthma who had airflow obstruction at the time of study. With this approach we wished to test the hypothesis that a single inhalation of an ICS causes an acute, dose-dependent potentiation of β2-adrenergic bronchodilation as assessed by spirometry. The associated airway vascular response was also determined by measuring Qaw.

Subjects

Never smokers with physician-diagnosed asthma were considered for the study. They were allowed to use inhaled controller medication (including ICSs) and rescue medication. At study entry, the subjects had to be clinically stable and to have an FEV1 of < 75% predicted (inclusion criterion). Exclusion criteria were the presence of cardiovascular disease and use of cardiovascular medications, pregnancy, use of oral controller medication for asthma (methylxanthines, systemic glucocorticosteroids, leukotriene modifiers), and an acute respiratory infection within 4 weeks before enrollment. Fifteen subjects who met these criteria were enrolled in the study. The protocol was approved by the Human Subject Research Office at University of Miami (protocol #20071188) and registered with clinicaltrials.gov (NCT01210170). All subjects provided written informed consent.

Measurements

The FEV1 served as an index of airway smooth muscle tone and Qaw as an index of airway vascular smooth muscle tone. FEV1 and FVC were measured by spirometry three times, and the tracing with the highest FVC value was used for analysis. Predicted normal values for FEV1 were taken from Crapo et al.8

Qaw was measured with a noninvasive, previously validated soluble inert gas uptake method.9,10 The method determines the uptake of dimethyl ether (DME) from the anatomic dead space during breath holds of different duration. From the decrease in expired DME concentration over time, DME uptake is obtained, and from it Qaw is calculated using Fick’s principle. Qaw is normalized for anatomic dead space volume and expressed as μL/min/mL. Duplicate measurements were obtained; this required < 5 min. Systemic BP, heart rate, and arterial oxygen saturation by pulse oximetry were monitored at each measurement point.

Protocol

Each subject made five morning visits to the research laboratory, separated by at least 5 days. The subjects were instructed to abstain from ingesting alcoholic beverages or using PDE5 inhibitors for at least 12 h before coming to the laboratory and from having coffee or caffeinated drinks in the morning of the study day. Finally, the subjects were asked to not use inhaled controller medication for at least 12 h and albuterol for at least 4 h before coming to the laboratory.

On visit 1 (screening), the subjects were informed about the study and signed an informed consent and the Health Insurance Portability and Accountability Act form B. If they qualified for the study based on medical and medication history, they performed spirometry. Subjects whose FEV1 as percent of predicted normal met the entry criterion were enrolled in the study. They were asked to return for four more visits (visits 2-5) for the following treatment protocols:

  • • Inhalation of 400 μg mometasone dry powder inhaler (DPI) 30 min before inhalation of 180 μg albuterol

  • • Inhalation of placebo 30 min before inhalation of 180 μg albuterol

  • • Simultaneous inhalation of 400 μg mometasone DPI and 180 μg albuterol

  • • Simultaneous inhalation of placebo and 180 μg albuterol

Using a double-blind design randomized for the order of treatment, the subjects inhaled, on different experiment days, 400 μg mometasone or placebo from identical DPI units provided by Merck & Co, Inc. Using a spacer, two puffs of HFA-albuterol (Ventolin) delivered by a metered-dose inhaler were administered 30 min or immediately after mometasone or placebo.

FEV1 and Qaw, along with systemic BP, heart rate, and oxygen saturation, were measured before mometasone or placebo inhalation and before and 15 min after albuterol inhalation except on the day when mometasone and albuterol were coadministered; on that day, the measurements were made before and 15 min after the mometasone/albuterol coadministration.

Statistical Analysis

Data were analyzed using JMP for Macintosh, version 4.0 (SAS Institute Inc). Multifactorial analysis of variance was used to determine overall differences among treatments, followed by a paired t test to identify specific pair differences and by the Tukey-Kramer test for differences among all pairs. Significance was accepted when P < .05.

The patient characteristics are listed in Table 1. All patients were long-term users of ICSs (two subjects receiving 500 μg fluticasone/50 μg salmeterol bid, five subjects receiving 250 μg fluticasone/50 μg salmeterol bid, seven subjects receiving 320 μg budesonide/9 μg formoterol bid). Their mean FEV1 was 1.81 ± 0.12 L (62% ± 3%) on the screening day. On the two treatment days when placebo or mometasone was administered 30 min before albuterol, the mean preplacebo and premometasone FEV1 and Qaw were similar to the corresponding prealbuterol values. There were no differences in mean prealbuterol FEV1 and Qaw among the four treatment days (Table 2). Similarly, there were no differences in mean systemic systolic and diastolic BP, heart rate, and oxygen saturation between the screening day values and the values obtained on the treatment days.

Table Graphic Jump Location
TABLE 1 ]  Patient Demographics

bpm = beats per min; F = female; M = male; sat O2 = arterial oxygen saturation.

Table Graphic Jump Location
TABLE 2 ]  Prealbuterol FEV1 and Qaw

N = 15. Data are presented as mean ± SE. No significant differences were found among the four protocols. Qaw = airway blood flow.

The immediate bronchodilator response to albuterol as assessed 15 min post drug administration was potentiated by the simultaneous administration of mometasone. In combination with placebo, albuterol increased mean FEV1 by 0.2 L (10%), whereas in combination with mometasone the response was significantly greater (0.32 L or 19%) (P < .05) (Table 3).

Table Graphic Jump Location
TABLE 3 ]  Effect of 400 μg Mometasone on Albuterol-Induced Bronchodilation

N = 15. Data are presented as mean ± SE. ΔFEV1 = change in FEV1 from immediately before to 15 min after a dose of 180 μg albuterol.

a 

P < .05 vs simultaneous placebo-albuterol.

When mometasone or placebo was administered 30 min before albuterol, the albuterol-induced change in mean FEV1 was 0.18 L (10%) after placebo and 0.27 L (16%) after mometasone (Fig 1, Table 3). The relative magnitude of the mometasone effect was less than after simultaneous drug administration, and the difference between mometasone and placebo was not statistically significant.

Figure Jump LinkFigure 1 –  ΔFEV1 15 min after the inhalation of 180 μg albuterol. −30 min indicates administration of placebo or mometasone 30 min before albuterol. Simultaneous is simultaneous administration of placebo or mometasone with albuterol. ΔFEV1 = % change in FEV1; M = 400 μg mometasone; PL = placebo.Grahic Jump Location

The vasodilator response to albuterol was quantitatively greater than the bronchodilator response and significant whether mometasone was administered simultaneously with or 30 min before albuterol. With placebo, albuterol had no effect on mean Qaw (−1.8 μL/min/mL or −2% and 0.2 μL/min/mL or 0%) (Fig 2, Table 4). The corresponding values for mometasone were 10.4 μL/min/mL or 30% and 7.7 μL/min/mL or 18% (P < .005 for both).

Figure Jump LinkFigure 2 –  ΔQaw 15 min after the inhalation of 180 μg albuterol N = 15. −30 min indicates administration of placebo or mometasone 30 min before albuterol. Simultaneous is simultaneous administration of placebo or mometasone with albuterol. *P < .005 vs corresponding placebos. ΔQaw = change in airway blood flow from immediately before to 15 min after 180 mg albuterol. See Figure 1 legend for expansion of other abbreviation.Grahic Jump Location
Table Graphic Jump Location
TABLE 4 ]  Effect of 400 μg Mometasone on Albuterol-Induced Vasodilation in the Airway

N = 15. Data are presented as mean ± SE. ΔQaw = change in airway blood flow from immediately before to 15 min after 180 μg albuterol.

a 

P < .005 vs corresponding placebo-albuterol.

To our knowledge, this is the first study to show that a single administration of an ICS can acutely potentiate inhaled albuterol-induced bronchodilation as assessed by spirometry in patients with moderate asthma. It has been previously reported that the acute bronchodilator response to formoterol was not enhanced by the coadministration of budesonide.11 That study included patients with acute asthma and the use of a long-acting β2-adrenergic agonist, whereas the patients had moderately severe stable asthma and were treated with a short β2-adrenergic agonist. These differences may explain the discrepancy between the two studies.

An acute interaction between an ICS and a β2-adrenergic agonist has previously been shown for airway vascular smooth muscle responsiveness as reflected by Qaw but not for airway smooth muscle responsiveness as reflected by FEV1.7 Steroid-naive patients with mild asthma with essentially normal lung function were enrolled in that study, precluding the possibility of detecting significant changes in FEV1 after albuterol administration. For that reason, we conducted the present study in patients with moderate asthma whose FEV1 was < 70% predicted.

Mometasone significantly potentiated the bronchodilator response to albuterol in these patients when the two drugs were administered simultaneously. The effect seems to wane by 30 min. When administered 30 min before albuterol, mometasone still enhanced the bronchodilator response to albuterol, but the magnitude of the effect was less and no longer statistically significant. This time course is consistent with the proposed mechanism whereby glucocorticoids acutely potentiate β2-adrenergic responsiveness through a nongenomic inhibition of the disposal of the β2-adrenergic agonist.14

We chose recommended doses of mometasone and albuterol for the study. Therefore, the results can be considered clinically relevant in terms of the acute interaction between the two airway drugs and the magnitude of the enhanced FEV1 response. The patients were not steroid naive. Indeed, all were regular users of ICSs and allowed to continue using the medication until 12 h before coming to the laboratory. This indicates that long-term ICS treatment does not negate the acute effect of an ICS on albuterol responsiveness.

The present study confirmed our previous observation that the Qaw response to albuterol is blunted in patients with asthma, suggesting the presence of endothelial dysfunction.12,13 The present study also showed that vascular reactivity can be restored with a single dose of an ICS, as previously reported by us.7 Unlike in a previous study showing that long-term ICSs can restore Qaw responsiveness to albuterol in steroid-naive patients with asthma,14 the patients with asthma using ICSs in the present investigation still had a blunted Qaw response to albuterol. Perhaps the difference can be explained by the fact that patients with mild asthma were included in the previous studies, whereas we recruited patients with moderately severe asthma with airflow obstruction in the present investigation. Patients with more severe asthma may be resistant to the vascular effects of long-term ICS therapy.

It is not clear why the acute ICS effect on albuterol-induced relaxation is greater for airway vascular smooth muscle than airway smooth muscle. There is a greater expression of the steroid-sensitive organic cation transporter OCT3 in human airway vascular smooth muscle than airway smooth muscle, and the acute inhibition of the cellular uptake of hydrophilic β2-adrenergic agonists by steroids is also greater in airway vascular smooth muscle.15 Although this could explain the differential nongenomic effect of mometasone on albuterol-induced vasodilation and bronchodilation in the present study, other mechanisms could also be involved.

We believe that the results obtained with mometasone in the present study reflect a class effect, because previous studies involving different ICSs also showed a potentiation of albuterol-induced vasodilation in the airway.716 However, an in vitro study has demonstrated potency differences among different glucocorticosteroids.17

In a meta-analysis, Rodrigo18 reviewed the rapid clinical effects of ICSs in acutely exacerbated asthma. In this setting, ICSs were found to have beneficial effects on peak flow, FEV1, and hospital admissions in patients receiving standard care (including β2-adrenergic agonists). Although our study focused on the acute interaction between ICSs and albuterol responsiveness in patients with stable asthma, its results are consistent with the meta-analysis.18 In contrast to bronchodilation, the clinical significance of the acute ICS effect on albuterol-induced vasodilation is less clear. Possibly, the enhanced vasodilation could accelerate the local clearance of inflammatory spasmogens in the airway.

Our study addressed an exciting and novel interaction between ICSs and β2-adrenergic agonists. Thus far, this interaction has only been confirmed physiologically for airway vascular smooth muscle. The present study extended this concept to airway smooth muscle, a more important target in the treatment of asthma. The results of this pilot study will have to be supported by an investigation involving a larger number of patients with ΔFEV1 as the primary outcome. Such a study combination of a short-acting β2-adrenergic agonist with an ICS could provide the basis for the development of new rescue formulations for patients with asthma.

Author contributions: A. W. is guarantor of the paper, taking responsibility for the integrity of the work as a whole, from inception to published article. E. S. M. contributed to patient management, data analysis, and drafting the manuscript; L. C. and J. A. contributed to patient management and data collection and revising the manuscript; and A. W. contributed to conceiving the idea, patient management, and drafting and revising the manuscript for intellectual content.

Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr Wanner has received investigator-initiated academic grants from GlaxoSmithKline; Forest Research Institute; Merck & Co, Inc; and AstraZeneca and serves on the Scientific Advisory Board of Aradigm Corporation. Dr Mendes and Mss Cadet and Arana have reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Role of sponsors: The sponsor had no role in the design of the study, collection and analysis of data, or preparation of the manuscript.

DME

dimethyl ether

DPI

dry powder inhaler

ICS

inhaled glucocorticosteroid

Qaw

airway blood flow

Iversen LL, Salt PJ. Inhibition of catecholamine uptake-2 by steroids in the isolated rat heart. Br J Pharmacol. 1970;40(3):528-530. [CrossRef] [PubMed]
 
Gründemann D, Schechinger B, Rappold GA, Schömig E. Molecular identification of the corticosterone-sensitive extraneuronal catecholamine transporter. Nat Neurosci. 1998;1(5):349-351. [CrossRef] [PubMed]
 
Horvath G, Sutto Z, Torbati A, Conner GE, Salathe M, Wanner A. Norepinephrine transport by the extraneuronal monoamine transporter in human bronchial arterial smooth muscle cells. Am J Physiol Lung Cell Mol Physiol. 2003;285(4):L829-L837. [CrossRef] [PubMed]
 
Horvath G, Lieb T, Conner GE, Salathe M, Wanner A. Steroid sensitivity of norepinephrine uptake by human bronchial arterial and rabbit aortic smooth muscle cells. Am J Respir Cell Mol Biol. 2001;25(4):500-506. [CrossRef] [PubMed]
 
Kumar SD, Brieva JL, Danta I, Wanner A. Transient effect of inhaled fluticasone on airway mucosal blood flow in subjects with and without asthma. Am J Respir Crit Care Med. 2000;161(3 pt 1):918-921. [CrossRef] [PubMed]
 
Mendes ES, Pereira A, Danta I, Duncan RC, Wanner A. Comparative bronchial vasoconstrictive efficacy of inhaled glucocorticosteroids. Eur Respir J. 2003;21(6):989-993. [CrossRef] [PubMed]
 
Mendes ES, Horvath G, Campos M, Wanner A. Rapid corticosteroid effect on β(2)-adrenergic airway and airway vascular reactivity in patients with mild asthma. J Allergy Clin Immunol. 2008;121(3):700-704. [CrossRef] [PubMed]
 
Crapo RO, Morris AH, Gardner RM. Reference spirometric values using techniques and equipment that meet ATS recommendations. Am Rev Respir Dis. 1981;123(6):659-664. [PubMed]
 
Wanner A, Mendes ES, Atkins ND. A simplified noninvasive method to measure airway blood flow in humans. J Appl Physiol (1985). 2006;100(5):1674-1678. [CrossRef] [PubMed]
 
Scuri M, McCaskill V, Chediak AD, Abraham WM, Wanner A. Measurement of airway mucosal blood flow with dimethylether: validation with microspheres. J Appl Physiol (1985). 1995;79(4):1386-1390. [PubMed]
 
Bateman ED, Fairall L, Lombardi DM, English R. Budesonide/formoterol and formoterol provide similar rapid relief in patients with acute asthma showing refractoriness to salbutamol. Respir Res. 2006;7:13. [CrossRef] [PubMed]
 
Brieva J, Wanner A. Adrenergic airway vascular smooth muscle responsiveness in healthy and asthmatic subjects. J Appl Physiol (1985). 2001;90(2):665-669. [PubMed]
 
Wanner A, Mendes ES. Airway endothelial dysfunction in asthma and chronic obstructive pulmonary disease: a challenge for future research. Am J Respir Crit Care Med. 2010;182(11):1344-1351. [CrossRef] [PubMed]
 
Mendes ES, Campos MA, Hurtado A, Wanner A. Effect of montelukast and fluticasone propionate on airway mucosal blood flow in asthma. Am J Respir Crit Care Med. 2004;169(10):1131-1134. [CrossRef] [PubMed]
 
Horvath G, Mendes ES, Schmid N, et al. The effect of corticosteroids on the disposal of long-acting beta2-agonists by airway smooth muscle cells. J Allergy Clin Immunol. 2007;120(5):1103-1109. [CrossRef] [PubMed]
 
Mendes ES, Rebolledo P, Wanner A. Acute effects of salmeterol and fluticasone propionate alone and in combination on airway blood flow in patients with asthma. Chest. 2012;141(5):1184-1189. [CrossRef] [PubMed]
 
Horvath G, Mendes ES, Schmid N, et al. Rapid nongenomic actions of inhaled corticosteroids on long-acting β(2)-agonist transport in the airway. Pulm Pharmacol Ther. 2011;24(6):654-659. [CrossRef] [PubMed]
 
Rodrigo GJ. Rapid effects of inhaled corticosteroids in acute asthma: an evidence-based evaluation. Chest. 2006;130(5):1301-1311. [CrossRef] [PubMed]
 

Figures

Figure Jump LinkFigure 1 –  ΔFEV1 15 min after the inhalation of 180 μg albuterol. −30 min indicates administration of placebo or mometasone 30 min before albuterol. Simultaneous is simultaneous administration of placebo or mometasone with albuterol. ΔFEV1 = % change in FEV1; M = 400 μg mometasone; PL = placebo.Grahic Jump Location
Figure Jump LinkFigure 2 –  ΔQaw 15 min after the inhalation of 180 μg albuterol N = 15. −30 min indicates administration of placebo or mometasone 30 min before albuterol. Simultaneous is simultaneous administration of placebo or mometasone with albuterol. *P < .005 vs corresponding placebos. ΔQaw = change in airway blood flow from immediately before to 15 min after 180 mg albuterol. See Figure 1 legend for expansion of other abbreviation.Grahic Jump Location

Tables

Table Graphic Jump Location
TABLE 1 ]  Patient Demographics

bpm = beats per min; F = female; M = male; sat O2 = arterial oxygen saturation.

Table Graphic Jump Location
TABLE 2 ]  Prealbuterol FEV1 and Qaw

N = 15. Data are presented as mean ± SE. No significant differences were found among the four protocols. Qaw = airway blood flow.

Table Graphic Jump Location
TABLE 3 ]  Effect of 400 μg Mometasone on Albuterol-Induced Bronchodilation

N = 15. Data are presented as mean ± SE. ΔFEV1 = change in FEV1 from immediately before to 15 min after a dose of 180 μg albuterol.

a 

P < .05 vs simultaneous placebo-albuterol.

Table Graphic Jump Location
TABLE 4 ]  Effect of 400 μg Mometasone on Albuterol-Induced Vasodilation in the Airway

N = 15. Data are presented as mean ± SE. ΔQaw = change in airway blood flow from immediately before to 15 min after 180 μg albuterol.

a 

P < .005 vs corresponding placebo-albuterol.

References

Iversen LL, Salt PJ. Inhibition of catecholamine uptake-2 by steroids in the isolated rat heart. Br J Pharmacol. 1970;40(3):528-530. [CrossRef] [PubMed]
 
Gründemann D, Schechinger B, Rappold GA, Schömig E. Molecular identification of the corticosterone-sensitive extraneuronal catecholamine transporter. Nat Neurosci. 1998;1(5):349-351. [CrossRef] [PubMed]
 
Horvath G, Sutto Z, Torbati A, Conner GE, Salathe M, Wanner A. Norepinephrine transport by the extraneuronal monoamine transporter in human bronchial arterial smooth muscle cells. Am J Physiol Lung Cell Mol Physiol. 2003;285(4):L829-L837. [CrossRef] [PubMed]
 
Horvath G, Lieb T, Conner GE, Salathe M, Wanner A. Steroid sensitivity of norepinephrine uptake by human bronchial arterial and rabbit aortic smooth muscle cells. Am J Respir Cell Mol Biol. 2001;25(4):500-506. [CrossRef] [PubMed]
 
Kumar SD, Brieva JL, Danta I, Wanner A. Transient effect of inhaled fluticasone on airway mucosal blood flow in subjects with and without asthma. Am J Respir Crit Care Med. 2000;161(3 pt 1):918-921. [CrossRef] [PubMed]
 
Mendes ES, Pereira A, Danta I, Duncan RC, Wanner A. Comparative bronchial vasoconstrictive efficacy of inhaled glucocorticosteroids. Eur Respir J. 2003;21(6):989-993. [CrossRef] [PubMed]
 
Mendes ES, Horvath G, Campos M, Wanner A. Rapid corticosteroid effect on β(2)-adrenergic airway and airway vascular reactivity in patients with mild asthma. J Allergy Clin Immunol. 2008;121(3):700-704. [CrossRef] [PubMed]
 
Crapo RO, Morris AH, Gardner RM. Reference spirometric values using techniques and equipment that meet ATS recommendations. Am Rev Respir Dis. 1981;123(6):659-664. [PubMed]
 
Wanner A, Mendes ES, Atkins ND. A simplified noninvasive method to measure airway blood flow in humans. J Appl Physiol (1985). 2006;100(5):1674-1678. [CrossRef] [PubMed]
 
Scuri M, McCaskill V, Chediak AD, Abraham WM, Wanner A. Measurement of airway mucosal blood flow with dimethylether: validation with microspheres. J Appl Physiol (1985). 1995;79(4):1386-1390. [PubMed]
 
Bateman ED, Fairall L, Lombardi DM, English R. Budesonide/formoterol and formoterol provide similar rapid relief in patients with acute asthma showing refractoriness to salbutamol. Respir Res. 2006;7:13. [CrossRef] [PubMed]
 
Brieva J, Wanner A. Adrenergic airway vascular smooth muscle responsiveness in healthy and asthmatic subjects. J Appl Physiol (1985). 2001;90(2):665-669. [PubMed]
 
Wanner A, Mendes ES. Airway endothelial dysfunction in asthma and chronic obstructive pulmonary disease: a challenge for future research. Am J Respir Crit Care Med. 2010;182(11):1344-1351. [CrossRef] [PubMed]
 
Mendes ES, Campos MA, Hurtado A, Wanner A. Effect of montelukast and fluticasone propionate on airway mucosal blood flow in asthma. Am J Respir Crit Care Med. 2004;169(10):1131-1134. [CrossRef] [PubMed]
 
Horvath G, Mendes ES, Schmid N, et al. The effect of corticosteroids on the disposal of long-acting beta2-agonists by airway smooth muscle cells. J Allergy Clin Immunol. 2007;120(5):1103-1109. [CrossRef] [PubMed]
 
Mendes ES, Rebolledo P, Wanner A. Acute effects of salmeterol and fluticasone propionate alone and in combination on airway blood flow in patients with asthma. Chest. 2012;141(5):1184-1189. [CrossRef] [PubMed]
 
Horvath G, Mendes ES, Schmid N, et al. Rapid nongenomic actions of inhaled corticosteroids on long-acting β(2)-agonist transport in the airway. Pulm Pharmacol Ther. 2011;24(6):654-659. [CrossRef] [PubMed]
 
Rodrigo GJ. Rapid effects of inhaled corticosteroids in acute asthma: an evidence-based evaluation. Chest. 2006;130(5):1301-1311. [CrossRef] [PubMed]
 
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