Airway responsiveness and airway remodeling after chronic exposure to procaterol and fenoterol in guinea pigs in vivo.
BACKGROUND
Chronic exposure to fenoterol (FEN), a beta(2)-adrenergic receptor (beta(2)-AR) agonist, was shown to induce both airway hyperresponsiveness and airway remodeling in experimental animals.


OBJECTIVE
We wanted to know the effects of chronic exposure to procaterol (PRO), a beta(2)-AR agonist, on airway function and structure, because this agent is widely used as a bronchodilator in Japan. For comparison, the effects of FEN were also examined.


METHODS
Aerosolized PRO (0.1 or 1 mg/ml), FEN (1 mg/ml) or vehicle (0.9% NaCl) was given to guinea pigs 3 times a day for 6 weeks. Sublaryngeal deposition of these agents was calculated using radioisotopes. At 72 h after the last inhalation of PRO, FEN or vehicle, the dose-response relationship between lung resistance (R(L)) and intravenously administered acetylcholine (ACh) was measured. After measuring R(L), histological changes in noncartilaginous airway dimensions were evaluated.


RESULTS
The amount of sublaryngeal deposition of 0.1 mg/ml PRO in the present study was speculated to be 100 times larger than that of therapeutic dose. ACh concentrations causing 2-fold, 10-fold and maximal increases in R(L) were not different in 4 groups tested. In the smaller membranous airways (<0.4 mm in diameter), but not the larger ones, thickening of adventitial areas was significantly greater in animals treated with beta(2)-AR agonists than in control animals (23 and 25, and 96% higher in animals treated with 0.1 and 1 mg/ml PRO or 1 mg/ml FEN, respectively). The degree of the increase was significantly less in PRO-treated animals than in FEN-treated animals (p < 0.01).


CONCLUSIONS
Our results did not provide any evidence that regular inhalation of PRO at the therapeutic dose might induce bronchial hyperresponsiveness. In addition, huge amounts of PRO only caused a mild thickening of the adventitial areas, suggesting that PRO may be a weak inducer of airway remodeling compared with FEN.
Nishimura
Hideko
H
Department of Pediatrics, Gunma University School of Medicine, Maebashi, Gunma, Japan.
Tokuyama
Kenichi
K
Arakawa
Hirokazu
H
Ohki
Yasushi
Y
Sato
Akira
A
Kato
Masahiko
M
Mochizuki
Hiroyuki
H
Morikawa
Akihiro
A
D000280:Administration, Inhalation; D000318:Adrenergic beta-Agonists / Q000008:administration & dosage / Q000633:toxicity; D000403:Airway Resistance / Q000187:drug effects*; D000818:Animals; D016535:Bronchial Hyperreactivity / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology; D001993:Bronchodilator Agents / Q000008:administration & dosage / Q000633:toxicity; D005280:Fenoterol / Q000008:administration & dosage / Q000633:toxicity*; D006168:Guinea Pigs; D008297:Male; D017265:Procaterol / Q000008:administration & dosage / Q000633:toxicity*
D000318:Adrenergic beta-Agonists; D001993:Bronchodilator Agents; D005280:Fenoterol; D017265:Procaterol