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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01216748
Recruitment Status : Completed
First Posted : October 7, 2010
Results First Posted : December 17, 2014
Last Update Posted : May 27, 2016
National Institutes of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Information provided by (Responsible Party):
Matthias Salathe, University of Miami

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

Condition or disease Intervention/treatment Phase
Healthy Volunteers Other: quiet breathing Other: Hypocapnic Hyperventilation Other: Hypercapnic Hyperventilation Other: eucapnic hyperventilation Not Applicable

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 10 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: Clinical Evidence of pH Dependent ß2 Adrenergic Transport Mechanisms in the Airway
Study Start Date : January 2010
Actual Primary Completion Date : July 2010
Actual Study Completion Date : August 2010

Arm Intervention/treatment
Experimental: health life-time non smokers
health lifetime non-smokers will be challenged with 4 respiratory maneuvers:quiet breathing, hypocapnic hyperventilation, hypercapnic hyperventilation, and eucapnic hyperventilation
Other: quiet breathing
Subjects were instructed to breath normally at room air.

Other: Hypocapnic Hyperventilation
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.

Other: Hypercapnic Hyperventilation
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

Other: eucapnic hyperventilation
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.

Primary Outcome Measures :
  1. Changes in Airway Blood Flow After 180μg Albuterol by Inhalation (ΔQaw) vs Baseline [ Time Frame: 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 :
  1. Exhaled Breath Condensate (EBC) pH Variation [ Time Frame: 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.

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01216748

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United States, Florida
Pulmonary Human Research Laboratory, University of Miami School of Medicine
Miami, Florida, United States, 33136
Sponsors and Collaborators
University of Miami
National Institutes of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
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Principal Investigator: Matthias Salathe University of Miami

Publications automatically indexed to this study by Identifier (NCT Number):
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Responsible Party: Matthias Salathe, Professor of Medicine, University of Miami Identifier: NCT01216748     History of Changes
Other Study ID Numbers: 20070583
R01HL060644 ( U.S. NIH Grant/Contract )
First Posted: October 7, 2010    Key Record Dates
Results First Posted: December 17, 2014
Last Update Posted: May 27, 2016
Last Verified: November 2014
Keywords provided by Matthias Salathe, University of Miami:
airway blood flow
Additional relevant MeSH terms:
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Adrenergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs