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J Appl Physiol 105: 54-57, 2008. First published May 8, 2008; doi:10.1152/japplphysiol.90334.2008
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Effect of an inhaled glucocorticoid on endothelial function in healthy smokers

Eliana S. Mendes,1 Gabor Horvath,1,2 Patricia Rebolledo,1 Maria Elena Monzon,1 S. Marina Casalino-Matsuda,1 and Adam Wanner1

1Division of Pulmonary and Critical Care Medicine, Department of Medicine, Miller School of Medicine, University of Miami, Miami, Florida; and 2Department of Respiratory Medicine, Semmelweis University School of Medicine, Budapest, Hungary

Submitted 27 February 2008 ; accepted in final form 1 May 2008


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Cigarette smoking is associated with attenuated endothelium-dependent vasodilation (endothelial dysfunction) in the systemic circulation, including the airway circulation. We wished to determine whether an inhaled corticosteroid could restore endothelial function in the airway of lung-healthy current smokers, ex-smokers, and nonsmokers. We measured baseline airway blood flow (Qaw) and Qaw reactivity to inhaled albuterol as an index of endothelium-dependent vasodilation and to sublingual nitroglycerin as an index of endothelium-independent vasodilation in lung-healthy current smokers, ex-smokers, and nonsmokers. Current smokers were then treated with inhaled fluticasone for 3 wk, and all measurements were repeated after fluticasone treatment and after a subsequent 3-wk fluticasone washout period. Baseline mean Qaw and endothelium-independent Qaw reactivity were similar in the three groups. Mean endothelium-dependent Qaw reactivity was 49.5% in nonsmokers, 42.7% in ex-smokers, and 10.8% in current smokers (P < 0.05 vs. nonsmokers). In current smokers, mean baseline Qaw was unchanged after fluticasone treatment, but endothelium-dependent Qaw reactivity significantly increased to 34.9%. Qaw reactivity was again blunted after fluticasone washout. Endothelial dysfunction, as assessed by vascular reactivity, can be corrected with an inhaled corticosteroid in the airway of lung-healthy current smokers. This proof of concept can serve as the basis for future clinical investigations on the effect of glucocorticoids on endothelial function in smokers.

airway blood flow; smoking

CIGARETTE SMOKING IS ASSOCIATED with attenuated vascular relaxation responses in the systemic circulation, and this defect has been related to cardiovascular disease (5, 30). The abnormal relaxation could be due to impaired vascular smooth muscle function or decreased stimulated endothelial nitric oxide (NO) release, a phenomenon that has been termed endothelial dysfunction. Impairments of both endothelium-independent vascular relaxation (assessed with nitroglycerin) and endothelium-dependent vascular relaxation (assessed with a β2-adrenergic agonist or flow-mediated vasodilation) have been reported, with the latter impairment being more consistent and of greater magnitude (1, 5, 31). Abnormal relaxation responses in smokers typically are demonstrated in the brachial artery, but other vascular beds, including the carotid and coronary arteries, are also involved, suggesting the presence of a global systemic vascular dysfunction (30, 31).

The airway vasculature is derived from the systemic circulation and, therefore, participates in the vascular dysfunction seen in smokers. We have previously reported that healthy smokers have a blunted vasodilator response to inhaled albuterol in the airway as an expression of endothelial dysfunction, with a partial recovery of albuterol responsiveness in healthy ex-smokers, but not in ex-smokers with chronic obstructive pulmonary disease (COPD) (21). In the subjects with COPD, inhalation treatment with a combined glucocorticoid/long-acting β-agonist preparation restored albuterol responsiveness. Because cigarette smoking and COPD have been associated with airway inflammation, it is likely that the glucocorticoid component of the treatment was responsible for the observed effect. However, because only albuterol responsiveness was assessed, it remained to be shown if the blunted vasodilator response was due to abnormal endothelium-dependent or endothelium-independent relaxation. Furthermore, that study only examined the treatment effect in COPD patients, not in healthy smokers.

Database studies have shown that acute cardiovascular events, such as acute myocardial infarction and cardiovascular death after hospitalization, are reduced in COPD patients who use inhaled corticosteroids (ICS) (13, 16, 17). This has been attributed to the ICS' effect on the systemic inflammation associated with COPD (18). Although a large multicenter prospective study of COPD patients, powered for mortality as the primary outcome, failed to show a reduction in all-cause mortality with combination therapy consisting of inhaled fluticasone and salmeterol, this finding did not rule out a potentially beneficial effect of such treatment on the incidence of nonfatal cardiovascular events (3).

The present study had two aims. First, we wished to determine whether lung-healthy current and ex-smokers have bronchial endothelial dysfunction by assessing airway blood flow (Qaw) responses to inhaled albuterol and sublingual nitroglycerin, agents that previously have been used to investigate endothelium-dependent and -independent relaxation in other systemic vascular beds (7, 8, 26). The second aim was to determine whether treatment with an ICS restores endothelial function.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Subjects.   We enrolled 15 current smokers with a >10 pack·yr history of smoking, 15 ex-smokers with a >10 pack·yr history of smoking who quit smoking >1 yr before the study, and 15 never smokers. The exclusion criteria were as follows: 1) a physician diagnosis of cardiovascular disease; 2) a physician diagnosis of COPD, asthma, bronchiectasis, and cystic fibrosis; 3) the use of cardiovascular or airway medication; 4) a body mass index >30; and 5) a forced expiratory volume (FEV) <80% of predicted and FEV-to-forced vital capacity ratio <0.7. All subjects had been free of an acute respiratory infection for at least 4 wk before beginning the study, and no subject had an acute respiratory infection during the study. The study was approved by the Western Institutional Review Board, and informed consent was obtained from the subjects.

Measurements.   To assess airway vascular relaxation responses, we determined Qaw, an index of airway vascular smooth muscle tone. Qaw was measured with a previously validated soluble inert-gas uptake method, normalized for the anatomical dead space, and expressed as microliters per minute per milliliter (27, 29).

FEV in 1 s (FEV1) was measured with a Koko spirometer (Ferraris Respiratory, Louisville, CO). Predicted normal values were taken from Crapo et al. (6).

Protocol.   There were two to four visits to the laboratory. All subjects had the first two visits, which were separated by at least 2 days. Current smokers had two additional visits. Current smokers were asked not to smoke before coming to the laboratory on the 4 study days. The subjects were instructed to abstain from ingesting alcoholic beverages the night before each study day and not to ingest coffee or caffeinated drinks for at least 12 h before the study. The subjects were also instructed not to use phosphodiesterase type 5 inhibitors for 12 h before coming to the laboratory. On each study day, the protocol started at the same time (in the morning).

On visit 1, the subjects first underwent spirometry, and then Qaw, blood pressure, and heart rate were measured before and 10 min after either 180 µg albuterol inhaled from a metered dose inhaler (MDI) with a spacer, or 400 µg sublingual nitroglycerin. The sequence in which the two drugs were administered on the 2 study days was randomly chosen.

On visit 2, the protocol of visit 1 was repeated with the alternate drug. After completion of the experiment on visit 2, current smokers were started on a 3-wk course of 220 µg fluticasone inhaled from a MDI with a spacer twice a day. The day after the last dose, these subjects returned to the laboratory for visit 3. At this visit, spirometry, Qaw, blood pressure, and heart rate were measured before and 10 min after 180 µg albuterol inhaled from an MDI with a spacer. Fluticasone was discontinued at this time, and 3 wk later the subjects returned to the laboratory for visit 4 to repeat the protocol of visit 3.

Statistical analysis.   Data were analyzed using JMP for Macintosh, version 4.0 (SAS Institute, Cary, NC). Multifactorial analysis of variance was used to determine overall differences among treatments, followed by a paired t-test to identify specific pair differences. Significance was accepted at P < 0.05.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
The demographic data for all subjects are summarized in Table 1. There were no significant differences in mean age, weight, spirometric values, blood pressure, or pulse rate among the three groups, and the smoking histories were comparable in the ex-smokers and current smokers. Similarly, mean baseline Qaw was similar in the three groups, and the pre-albuterol and pre-nitroglycerine Qaw values remained the same at the three time points in current smokers (Table 2). Mean blood pressure (diastolic blood pressure plus one-third of pulse pressure), mean blood pressure/Qaw, and heart rate did not change after vasodilator administration in any group, nor did they change among the different time points in smokers (Table 3). Therefore, vasodilator responses were expressed as change in Qaw.


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  		Table 1. Demographics and baseline parameters (visit 1)

 

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  		Table 2. Prevasodilation Qaw in nonsmokers, ex-smokers, and current smokers

 

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  		Table 3. Hemodynamic parameters before and after vasodilator in smokers

 
While Qaw responsiveness to nitroglycerin was not different among the three groups, Qaw responsiveness to albuterol was significantly lower in current smokers than nonsmokers, with ex-smokers showing a tendency toward having a lower value than nonsmokers (Fig. 1).


Figure 1
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  		Fig. 1. Airway blood flow (Qaw) response to albuterol (ALB) and nitroglycerin (NTG) in nonsmokers, ex-smokers, and current smokers (smokers). ALB+ICS, albuterol response after fluticasone treatment (inhaled corticosteroids). ALB+Wo, albuterol response after fluticasone washout. *P < 0.05 vs ALB response in nonsmokers and ex-smokers.

 
In current smokers, treatment with fluticasone restored Qaw responsiveness to albuterol; this effect was no longer seen 3 wk after fluticasone treatment had been discontinued.

Albuterol and nitroglycerine and fluticasone treatment had no effect on spirometric values, including FEV1 in smokers (Table 4).


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  		Table 4. FEV1 before and after albuterol and nitroglycerine in smokers

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
This is the first study to show that the endothelial dysfunction seen in healthy current smokers can be reversed with a glucocorticoid. The results also showed that the glucocorticoid effect wanes after the treatment is discontinued. Endothelial function was assessed in the airway, and the glucocorticoid treatment was also directed to the airway. It has been well established that cigarette smokers have systemic endothelial dysfunction (4, 23); however, whether inhaled glucocorticoids might restore endothelial function in the systemic circulation outside the airway remains to be investigated. The glucocorticoid's action on the airway circulation may qualitatively differ from its action in other vascular beds, and the glucocorticoid concentration needed to restore endothelial function may not be reached outside the airway when the drug is administered by inhalation, as was the case in the present study. In previous investigations in which glucocorticoids were administered systemically for several days, no consistent effects were found on endothelium-dependent relaxation in the brachial artery (19, 20). However, those experiments addressed the actions of glucocorticoids on endothelial function in healthy nonsmokers, not on smoking-associated endothelial dysfunction, as in the present study.

There was a difference in endothelium-dependent (albuterol-induced) vascular relaxation, but not in endothelium-independent (nitroglycerin-induced) vascular relaxation among the three groups, indicating that the blunted albuterol response and its restoration after glucocorticoid treatment in current smokers reflected endothelial dysfunction. We believe that the observed changes in Qaw in response to albuterol and nitroglycerine reflected local vasodilation, because the perfusion pressure (mean systemic blood pressure) remained unchanged throughout the study in all of the groups. Similarly, prevasodilator Qaw was the same at all time points.

FEV1 was normal before fluticasone treatment and remained unchanged after fluticasone and fluticasone washout. It, therefore, is not likely that, in the current smokers, fluticasone changed airway geometry sufficiently to influence Qaw responsiveness to albuterol due to changes in albuterol deposition.

Since endothelial dysfunction in smokers has been attributed to oxidative stress, due to either oxidants contained in cigarette smoke or inflammation-related endogenenous oxygen radical generation, attempts have been made to treat endothelial dysfunction with antioxidants. Those interventions have resulted in transient or no improvements in endothelium-dependent vascular relaxation in smokers or individuals with hypercholesterolemia (9, 22). It has been reported that ICS treatment lowers exhaled H2O2 concentrations in patients with COPD (11, 28). Possibly, ICS treatment had a similar effect on oxidative stress and restored endothelial function through this mechanism in our smokers.

Other glucocorticoid actions also could have been operative (25). For example, it has been reported that high-dose glucocorticoids resulting in serum dexamethasone concentrations of ~140 nmol/l can activate endothelial NO synthase (NOS) through a nontranscriptional action (12, 15). The long-term, low-dose ICS treatment in our current smokers [estimated airway tissue fluticasone concentration of 20–40 nmol/kg (10)] could have upregulated endothelial NOS expression and potentiated its response to albuterol. This remains speculative at this time, as conflicting results have been obtained in different cell preparations in which the effects of high-dose glucocorticoids on NOS expression were investigated (2, 24).

Both the effects of cigarette smoking on endothelium-dependent vascular relaxation and the restoration of endothelial function in smokers seem to be reversible based on the results of our study. Endothelium-dependent relaxation was essentially normal in healthy ex-smokers, and the glucocorticoid effect on this function in healthy current smokers was lost after the 3-wk drug washout period. The former observation is in keeping with our laboratory's previous study involving healthy ex-smokers, and the latter observation confirms the previously seen reversible glucocorticoid effect on albuterol-induced relaxation in patients with COPD (21).

Endothelial dysfunction has been defined as disturbed endothelium-dependent relaxation of resistance vessels, breakdown of the microvascular endothelial barrier, and/or anti-adhesive function (14). We only assessed the effect of an inhaled glucocorticoid on endothelium-dependent relaxation in our study. It is not known if the treatment benefited the other elements of endothelial dysfunction, nor is it known if the observed actions on relaxation was a molecule-specific or class effect. The present investigation can be considered as providing proof of concept by demonstrating that endothelium-dependent vascular relaxation can be restored with an inhaled glucocorticoid in healthy cigarette smokers. Additional studies will be required to assess the role of ICS treatment in the overall context of cigarette smoke-induced endothelial dysfunction.


   FOOTNOTES
 

Address for reprint requests and other correspondence: E. S. Mendes, Miller School of Medicine, Univ. of Miami, Rm. 7064-A, 1600 NW 10th Ave., Miami, FL 33136 (e-mail: emendes{at}med.miami.edu)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


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 METHODS
 RESULTS
 DISCUSSION
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