Changes in β2-adrenoceptor and other signaling proteins produced by chronic administration of ‘β-blockers’ in a murine asthma model

Abstract

These data suggest that in the murine model of asthma, several compensatory changes associated with either increased bronchodilator signaling or decreased bronchoconstrictive signaling, result from the chronic administration of certain 'beta-blockers'.

β 2 -Adrenoceptor signaling is required for the development of an asthma phenotype in a murine model

“…We had also reported an up-regulation of ␤ 2 -ARs after chronic ␤-AR inverse agonist treatment and speculated this may be partially responsible for the attenuation of the asthma phenotype (25). However, the results with the ␤ 2 -AR Ϫ/Ϫ mice also rule out receptor up-regulation as necessary for attenuation of the asthma phenotype.…”

“…Based on the paradigm shift that occurred in chronic CHF therapy, we investigated whether chronic treatment with ␤ 2 -AR inverse agonists, a class of drugs currently contraindicated in asthma because of their potential to produce acute bronchoconstriction, may be beneficial with long-term administration (14,15,25,26). Indeed, we found that chronic treatment with ␤ 2 -AR inverse agonists produced a time-dependent decrease in AHR and mucous metaplasia in a murine model of asthma (14,15), whereas treatment with alprenolol, a ␤-blocker without inverse agonist properties, did not decrease AHR (15).…”

Response to salbutamol in patients with mild asthma treated with nadolol

“…However, patients can be functionally inoperable due to comorbidity, advanced age, multiple primary lesions or irresectable, centrally localised tumours, or because they refuse surgery [2]. Therefore, varieties of endoscopic techniques, such as photodynamic therapy, cryotherapy, laser therapy, electrocautery and brachytherapy, were developed as alternatives to surgery [3][4][5]. The combination of high-dose external-beam radiotherapy (EBRT) with intraluminal radiotherapy (IR) using low [6][7][8], middle [9] and high dose-rate [10] iridium-192, has been investigated in ROLC with promising results.…”

“…The effect of chronic administration of b-blockers in asthma has remained unknown until recently, when studies on a murine model of asthma showed that, while acute (singledose) administration of b-blockers increased airway hyperresponsiveness (AHR), their chronic (28-day) administration had an opposite effect and decreased AHR [3]. Furthermore, recent data demonstrate that chronic b-blocker treatment produces broad anti-inflammatory effects, and especially dramatic effects on airway epithelium and mucous metaplasia [4,5]. More recently, our group has further confirmed the pivotal role that b 2 -ADR has on mucous metaplasia using a b 2 -ADR null mouse [6].…”

Agonizing over agonism: Should asthmatics turn their β-receptors on or off?

“…Another interesting possibility is high-affinity ␤ 2 AR agonists, which could effectively compete with ␤ 2 AR inverse agonists for occupancy of ␤ 2 ARs on airway smooth muscle to promote bronchorelaxation. Moreover, the signaling capacity of agonist-activated ␤ 2 ARs is predicted to be increased as a result of chronic treatment with ␤ 2 AR inverse agonists, which causes an up-regulation of ␤ 2 AR density in the lung (16).…”