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Effect of chronic administration of B2 adrenoceptor agonists on airway responsiveness in guiner pigs

University of British Columbia

We tested the hypothesis that regular inhaled ß₂ adrenergic receptor (ß₂AR) agonist administration increases airway responsiveness in guinea pigs. Fenoterol hydrobromide, in sub-laryngeal doses equivalent to human therapeutic doses on a weight basis (5.281ɥg/kg), was administered by nebulizer three times a day for six weeks to normal adolescent guinea pigs (FEN, n=10), and to ovalbumin sensitized guinea pigs during the process of induction of allergic airway hyperresponsiveness to ovalbumin and throughout subsequent repeated antigen challenge periods (OA+FEN, n=20). Controls included saline-treated normal animals (CON, n10) and ovalbumin-sensitized animals treated with repeated antigen challenge and saline (OA, n=20). Bromodeoxyuridine (BrdU) was administered to all guinea pigs repeatedly to detect airway wall tissue proliferation. Pulmonary resistance (RL) versus nebulized acetyicholine (ACh) was recorded. Small airway dimensions were measured. Area fractions of cell nuclei and BrdU positive nuclei in small airway were measured. BrdU-incorporated DNA from lung was extracted and quantified by slot blot. RLmax increased 2-fold and the ACh concentration causing a 10-fold increase in RL (PC 10) decreased 4-fold, in FEN, OA, and OA+FEN groups compared to the CON group. In the FEN, OA and OA+FEN groups, in vitro tracheal smooth muscle contractile responses to maximal concentrations of acetyicholine increased 2-fold and this increase was not due to increased smooth muscle mass (cross-sectional muscle area). There was no evidence for ß₂AR desensitization as judged by in vitro tracheal smooth muscle relaxant responses to fenoterol. The outer wall areas were significantly increased in FEN, OA and OA+FEN compared with CON. Although the inner wall area was not increased, the smooth muscle proliferation index was increased following OA, but not FEN and there was an increased number of BrdU positive granulocytes in the epithelium and adventitial layers following OA. Increased BrdU incorporation into DNA following OA was detected on slot blot. There was no difference in the proliferation index of epithelial cells between control and FEN or OA-treated groups. These results suggest that chronic32AR stimulation increases airway smooth muscle contractility and in vivo airways responsiveness to a degree similar to that induced by chronic antigen exposure. Although no evidence was obtained in support of a fenoterol-induced inflammatory cell influx or proliferative stimulus, the increased outer wall area, by altering the interrelationships between airway geometry and airway-parenchymal interdependence, may contribute to the excessive airway narrowing induced by fenoterol.

Thesis/Dissertation

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2009-02-23

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http://hdl.handle.net/2429/4957

Medicine

University of British Columbia

UBCV

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