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

Not Applicable

Completed

Interventions: Other: quiet breathing
Other: Hypocapnic Hyperventilation
Other: Hypercapnic Hyperventilation
Other: eucapnic hyperventilation

Brief Summary: The purpose of this study was to determine if airway pH has an effect on albuterol-induced vasodilation in the airway. Methods: Ten healthy volunteers performed the following respiratory maneuvers: quiet breathing, hypocapnic hyperventilation, hypercapnic hyperventilation, and eucapnic hyperventilation

Detailed Description: 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.

Recruitment & Eligibility

Inclusion Criteria

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

Arm && Interventions

Group	Intervention	Description
health life-time non smokers	Hypocapnic Hyperventilation	health lifetime non-smokers will be challenged with 4 respiratory maneuvers:quiet breathing, hypocapnic hyperventilation, hypercapnic hyperventilation, and eucapnic hyperventilation
health life-time non smokers	eucapnic hyperventilation	health lifetime non-smokers will be challenged with 4 respiratory maneuvers:quiet breathing, hypocapnic hyperventilation, hypercapnic hyperventilation, and eucapnic hyperventilation
health life-time non smokers	quiet breathing	health lifetime non-smokers will be challenged with 4 respiratory maneuvers:quiet breathing, hypocapnic hyperventilation, hypercapnic hyperventilation, and eucapnic hyperventilation
health life-time non smokers	Hypercapnic Hyperventilation	health lifetime non-smokers will be challenged with 4 respiratory maneuvers:quiet breathing, hypocapnic hyperventilation, hypercapnic hyperventilation, and eucapnic hyperventilation

Primary Outcome Measures

Name	Time	Method
Changes in Airway Blood Flow After 180μg Albuterol by Inhalation (ΔQaw) vs Baseline	15 minutes after albuterol inhalation	Effect of airway pH on albuterol responsiveness as reflected by the change in airway blood flow after 180μg albuterol by inhalation (ΔQaw) vs baseline.

Secondary Outcome Measures

Name	Time	Method
Exhaled Breath Condensate (EBC) pH Variation	10 minutes after each respiratory manouver.	EBC samples were collected at each respiratory maneuver by directing the subject's exhaled breath into a pre-cooled (-10C) tube for 10 min. pH was measured immediately after collection.