Clinical Evidence of pH Dependent ß2 Adrenergic Transport Mechanisms in the Airway

The lungs provide a unique absorptive surface for drug delivery. Many inhaled drugs are rapidly absorbed into the airway because of their lipophilic chemical characteristics. However, the majority of the currently used β2-adrenergic bronchodilators cannot freely diffuse across the epithelial cell membrane because of their transient or permanent positive charge at physiological pH. Inhaled albuterol, a β2-adrenergic agonist used widely for the treatment of obstructive airway disease, is charged positively in neutral or acidic conditions and thus requires active transport across the airway epithelium. Previous studies in the lab have shown that albuterol uptake into airway epithelia occurs via a pH sensitive cation transporter (OCTN2). The vasodilator response to an inhaled β2-adrenergic agonist could be an expression of epithelial cation transport. The investigators propose that the magnitude and duration of vasodilation in the airway caused by an inhaled hydrophilic β2-adrenergic agonist such as albuterol may be altered by changes in airway pH. The purpose of this protocol is to determine the effect of ASL pH on the response of Qaw to inhaled albuterol by manipulating airway pH through ventilatory maneuvers in health subjects: hyperventilation to raise pH and ventilation with CO2 bleed-in to lower pH.

Inclusion criteria

• Lifetime non-smokers
• FEV1 > 80% predicted value and FEV1/FVC > 0.75

Exclusion criteria

• Cardiovascular disease or use of cardiovascular or vasoactive drugs;
• Lung disease or use of airway drugs (i.e. inhaled corticosteroids, β adrenergic agonists);
• Respiratory infection during the 4 weeks preceding the study
• Use of systemic glucocorticoids within 4 weeks of the study
• Pregnant or nursing females