Acute Effect of Mometasone on Beta-adrenergic Airway and Airway Vascular Relaxation in Severe Asthma

Overview

Glucocorticosteroids inhibit the disposal of organic cations by blocking organic cation transporters expressed by non-neuronal cells, thereby interfering with the inactivation of the organic cations by intracellular enzymes. Beta2-adrenergic agonists are organic cations, and the concentration of inhaled beta2-adrenergic agonists at beta2-adrenergic receptor sites on smooth muscle is likely to be increased by inhaled glucocorticosteroids (ICS) by the ICS' effect on the glucocorticosteroid-sensitive organic cation transporters. The investigators have shown in human airway vascular smooth muscle cells that the glucocorticosteroid action on organic cation uptake occurs within minutes, does not involve gene transcription or protein synthesis, is not mediated through classical steroid receptors, and is cell membrane-linked. In the present proposal, the investigators wish to use different single doses of mometasone, a clinically effective ICS, administered with or at different times before albuterol inhalation in subjects with moderate persistent asthma who are obstructed at the time of study. With this approach the investigators will test the hypothesis that a single inhalation of mometasone causes an acute, transient, dose-dependent potentiation of beta2-adrenergic bronchodilation. If the hypothesis that a single dose of mometasone acutely potentiates beta2-adrenergic bronchodilation is correct, the results would have a significant impact on treatment strategies involving ICSs and beta2-adrenergic agonists in patients with asthma.

Fifteen non-smokers (males and females between the ages of 18 and 65 years) with physician-diagnosed moderate persistent asthma will be recruited for the study. The subjects will be allowed to use inhaled controller (including ICS) and rescue medication. At study entry, all asthmatic subjects must be clinically stable, and have a forced pre-bronchodilator one-second expired volume (FEV1) of \< 75% predicted. Approval for the protocol will be requested from the University of Miami Institutional Review Board. All subjects will provide written informed consent. Exclusion criteria: * Cardiovascular disease and use of cardiovascular medications * Pregnancy * Use of oral controller medication for asthma (methylxanthines, systemic glucocorticosteroids, leukotriene modifiers) * An acute respiratory infection within 4 weeks before enrollment. Each subject will make 8 visits to the research laboratory. Procedures: Visit 1 (screening visit): On this visit, after having signed the consent form, the subjects will perform spirometry before and 15 min after inhaling 180 µg albuterol from a HFA-MDI using a spacer. Visit 2-8:Subjects that qualify for the study will be asked to return for 7 more visits for the following treatment protocols: * Inhalation of 400 µg mometasone 30 min before inhalation of 180 µg albuterol * Inhalation of mometasone placebo 30 min before inhalation of 180 µg albuterol * Simultaneous inhalation of 400 µg mometasone and 180 µg albuterol * Simultaneous inhalation of mometasone placebo and 180 µg albuterol Systemic blood pressure, pulse, O2 saturation, spirometry and airway blood flow ( Qaw) will be measured before mometasone or placebo inhalation, and before and 15 min after albuterol inhalation except on the day when mometasone and albuterol are co-administered; on that day the measurements will be made before and 15 min after the mometasone/albuterol co-administration.