| Summary: | 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. === Medicine, Faculty of === Graduate
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