Effect of an Inhaled Glucocorticoid-long-acting Beta Adrenergic Agonist on Endothelial Function in COPD

To test the premise and to characterize the time dependence of the responses, the
investigators propose the following two aims:

1. To determine the effect of a medium dose glucocorticoid/long-acting beta-agonist
preparation (250 μg fluticasone plus 50 μg salmeterol) administered for 3 weeks on
inhaled albuterol and sub-lingual NTG induced vasodilation in the bronchial artery, as
assessed by ΔQaw in stable glucocorticoid-naïve COPD patients, and to re-assess the
responses after a 3 week glucocorticoid/long-acting beta-agonist washout period.

2. To determine inhaled albuterol and sub-lingual NTG-induced vasodilation (ΔQaw) before,
and 30 min and 120 min after a single medium dose of an ICS (220 μg fluticasone) in
stable glucocorticoid- naïve COPD patients.

For both aims, the protocol design will be placebo-controlled and double-blind. For the
second aim, only fluticasone pretreatment will be possible because the salmeterol component
of the fluticasone/salmeterol combination preparation could influence albuterol
responsiveness irrespective of any glucocorticoid effect. The timing of the endothelial
function measurements in the long-term glucocorticoid/long-acting beta-agonist protocol and
single dose ICS protocol is based on the past experience with ICS on airway vascular
function. Single dose effects were seen within 15-30 min and waned by 90 min (25,26), while
long-term treatment effects were no longer seen 3 weeks after ICS withdrawal (16).

Inclusion Criteria:

- Smoking history of at least 10 pack-years and to have quit smoking at least 1 year
before the study. -Diagnosis of COPD

- Post-bronchodilator FEV1 of less than 75% of predicted and FEV1/FVC ratio less than
0.7 (GOLD stage ≥2).

- At entry into the study, the subjects will have to be clinically stable; they will be
allowed to use short-acting and long-acting β2 - adrenergic agonists and cholinergic
antagonists as their usual airway medication.

Exclusion Criteria:

- Women of childbearing potential who do not use accepted birth control measures;
pregnant and breast feeding women.

- Use of cardiovascular medications that cannot be held on the study days

- Use of oral airway medications or anti-inflammatory agents

- Subjects with known beta-adrenergic agonist or NTG intolerance

- Acute respiratory infection within four weeks prior to the study

- A body mass index > 30