Bronchodilator effects on mechanisms involved in airway responsiveness
AuthorWitt-Enderby, Paula Ann.
Committee ChairYamamura, Henry
MetadataShow full item record
PublisherThe University of Arizona.
RightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
AbstractThe traditional approach to treating asthma includes the use of bronchodilator drugs, in particular β₂-adrenergic agonists and anti-cholinergics. It has been shown clinically that regularly scheduled use of both types of bronchodilators may result in a worsening of asthma. This dissertation evaluates the pulmonary effects of long-term bronchodilator administration in our animal model, the rabbit, at the level of the β-adrenergic receptor (βAR) and muscarinic cholinergic receptor (mAChR) located on airway smooth muscle. A four week infusion of the β₂ agonist bronchodilator, albuterol (6 mg/kg/day), resulted in a desensitization (lower affinity) and down-regulation of the βAR in tracheal smooth muscle (predominantly β₂ βAR subtype), mainstem bronchial smooth muscle (predominantly β₂ PAR subtype), and peripheral lung (predominantly β₁ βAR subtype) with no change in either affinity or βAR number in heart (predominantly β₁ βAR) as determined by radioligand binding analysis using the radioligand dihydroalprenolol ([³H] DHA). However, the βAR were not desensitized functionally in that isoproterenol-induced relaxations were not significantly different from control. In contrast, the functional response of the mAChR was increased significantly as compared to control in that the efficacy of methacholine-induced contractions was increased in mainstem bronchial and similarly in tracheal rings. However, the affinity and density of mAChR were not significantly different from the control values as determined by radioligand binding analysis using the radioligand quinuclidinyl benzilate ([³H] QNB). Chronic anti-cholinergic bronchodilator exposure using atropine (4 mg/kg/day) resulted in an increase in the efficacy of methacholine-induced contractile response of mainstem bronchial and tracheal rings with a concomitant increase in mAChR density in both tissues. Differential regulation of the mAChR may be occurring as demonstrated by experiments which show that chronic atropine exposure increased the M₃ mAChR subtype density to a greater extent than the M₂ mAChR subtype. This suggests that the methacholine-induced hyperresponsiveness seen clinically with chronic anti-cholinergic bronchodilator therapy may be due to an up-regulation of the M₃ mAChR in airway smooth muscle involved in bronchoconstriction.
Degree ProgramPharmacology & Toxicology