Chronic fenoterol exposure increases in vivo and in vitro airway responses in guinea pigs.

Abstract

We tested the hypothesis that the regular inhalation of a beta 2-adrenergic receptor (beta 2AR) agonist increases airway responsiveness in guinea pigs. A potent beta 2AR agonist, fenoterol hydrobromide, in sublaryngeal doses equivalent to maximal doses used in the treatment of asthma on a weight basis (5.28 micrograms/kg), was administered by nebulizer three times a day for 6 weeks to normal adolescent guinea pigs (FEN, n = 10) and to ovalbuminsensitized guinea pigs challenged twice weekly with ovalbumin (OA + FEN, n = 20), although not in the 12 h prior to or 4 h after antigen challenge. Controls included saline-treated normal animals (CON, n = 10) and ovalbumin-sensitized animals treated with repeated antigen challenge and saline (OA, n = 20). At 72 h after the last administration of saline, fenoterol, and ovalbumin, the dose-response relationship between pulmonary resistance (RL) and nebulized acetylcholine (ACh) was measured. RLmax increased 2-fold and the ACh concentration causing a 10-fold increase in RL (PC10) decreased 4-fold in the FEN, OA, and OA + FEN groups as compared to the CON group. In the FEN, OA, and OA + FEN groups, in vitro tracheal smooth-muscle contractile responses to maximal concentrations of acetylcholine increased 2-fold, and this increase was not due to increased smooth-muscle mass. There was no evidence for beta 2AR desensitization as judged by in vitro tracheal smooth-muscle relaxant responses to fenoterol. These results suggest that chronic beta 2AR stimulation increases airway smooth-muscle contractility and in vivo airways responsiveness to a degree similar to that induced by chronic antigen exposure. A similar effect in human asthmatics may explain the adverse effects observed during prolonged treatment with these drugs.

In vitro sensitization of human bronchus by β2-adrenergic agonists

“…We found that prolonged exposure of human bronchi to fenoterol affects maximal efficacy of ET-1 but not its potency. Our results are in agreement with the work reported by Wang and colleagues (60), who showed that chronic fenoterol exposure increased maximal airway response to ACh but not ACh EC 50 in guinea pigs. Potency of an agonist depends in part on the affinity of receptors for binding the agonist and in part on the efficiency with which agonist-receptor interaction is coupled to response.…”

“…Studies in animals and humans showed that chronic exposure to fenoterol or salbutamol induces a nonspecific bronchial sensitization, whereas the relaxant effects of these ␤ 2 -agonists on the airway smooth muscle are not decreased (11,59,60). The bronchial sensitization induced by fenoterol is similar to the sensitization provoked by ovalbumin in sensitized guinea pigs (60). Chronic administration of salbutamol at low doses to guinea pigs increases airway reactivity to histamine and methacholine (11).…”

Effect of salbutamol on pulmonary responsiveness in chronic pulmonary allergic inflammation in guinea pigs

“…Few experimental studies have investigated the effects of ß 2 -agonists on the inflammatory response in animal models of chronic allergic inflammation. The inhalation of environmental allergens is a major mechanism of asthma, and experimental models with allergen-induced chronic airway inflammation are probably more relevant to the study of the mechanisms of human asthma than models with a single challenge (19). In a previous study, we assessed the effects of airway inflammation induced by repeated OVA aerosol exposures in guinea pigs (16).…”

“…In guinea pigs the regular use of ß 2 -agonists induces airway narrowing and an increase in smooth muscle contractility (19). This treatment can also contribute to the increase of bronchial responsiveness (9) due to the reduction of constitutive adrenergic effects by either receptor down-regulation and/or decrease of receptor turnover, both reducing the receptor density on the cell surface.…”

Treatment with High Doses of Terbutaline Induces β-Adrenergic Desensitization of Guinea Pig Trachea Not Prevented by the Addition of Dexamethasone

“…However, the airway smooth muscle appears to have a special resistance to β 2 -adrenergic desensitization, probably due to a rapid turnover of the β 2 -adrenergic receptors [21]. Some studies, using low or medium doses, failed to find desensitization of the guinea pig trachea, although they demonstrated an increase in the response to metacholine or acetylcholine after in vivo salbutamol [22]or in vivo and in vitro fenoterol [23]treatment of guinea pigs. Moreover, an increase in airway responsiveness to indirectly acting stimuli after regular treatment with salbutamol or terbutaline has been described in asthmatic patients [24, 25].…”