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

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Healthy Volunteers

Intervention / Treatment
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* Other: quiet breathing
* Other: Hypocapnic Hyperventilation
* Other: Hypercapnic Hyperventilation
* Other: eucapnic hyperventilation


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: health life-time non smokers<br>health lifetime non-smokers will be challenged with 4 respiratory maneuvers:quiet breathing, hypocapnic hyperventilation, hypercapnic hyperventilation, and eucapnic hyperventilation | Other: quiet breathing<br>* Subjects were instructed to breath normally at room air.<br>Other: Hypocapnic Hyperventilation<br>* hypocapnic hyperventilation, the subjects were instructed to breathe fast and deep until their end-tidal pCO2 fell to 30 mmHg, corresponding to a systemic pH increase of about 0.1 pH units.<br>Other: Hypercapnic Hyperventilation<br>* For hypercapnic hyperventilation, a modification of a previously described procedure (15). While monitoring SaO2 using pulse oximetry and end-tidal CO2 by mass-spectrometry on a breath by breath basis, CO2 was bled into the inspired air to achieve an end-tidal pCO2 of at least 55 mmHg<br>Other: eucapnic hyperventilation<br>* For eucapnic hyperventilation, the subjects were instructed to increase their ventilation to the highest level of ventilation recorded in the previous two hyperventilation maneuvers, while CO2 was bled into the inspired air to maintain end-tidal pCO2 at 40 mmHg.<br>|

What is the study measuring?
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Primary Outcome Measures

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

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Exhaled Breath Condensate (EBC) pH Variation | 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. | 10 minutes after each respiratory manouver. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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airway blood flow, albuterol, acidosis, alkalosis