Artesunate attenuates airway resistance in vivo and relaxes airway smooth muscle cells in vitro via bitter taste receptor-dependent calcium signalling

摘要

Following the surprising discovery that bitter taste receptors (TAS2Rs) expressed in the lung and can be stimulated to relax airway smooth muscle cells (ASMCs), there is great interest in searching for a bitter taste receptor agonist as a new bronchodilator for asthma therapy. Among the great many other natural bitter substances, artesunate is of special interest to be evaluated for this purpose because of its pharmacological value as a derivative from the well-known anti-malarial, artemisinin. Therefore, in this study we treated either normal or ovalbumin (OVA)-induced asthmatic Balb/c mice in vivo with artesunate (30, 60 or 120 mu g) via aerosol inhalation. Subsequently, we measured the airway resistance of the mice in the presence or absence of artesunate. In addition, we treated either mouse or human ASMCs cultured in vitro with artesunate (0.25-2.0 mM) and then measured the traction force and [Ca2+](i) flux of the cells in the presence or absence of artesunate. The results demonstrate that artesunate attenuated airway resistance in a dose-dependent manner in both the normal and the OVA-treated mice, but more potently in the latter. The in vivo efficacy of artesunate at 120 mu g was comparable to that of the conventional bronchodilator, salbutamol, at 3 mu g in terms of the reduction in airway resistance. Artesunate also reduced traction force and induced an increase in [Ca2+](i) in the cultured ASMCs, which was mediated, at least in part, by TAS2R signalling in the human ASMCs. These results together suggest that artesunate might potentially be a cheap and safe bronchodilator to complement the current therapy of asthma.