Bitter Taste Receptor Agonists As A Novel Class Of Bronchodilators In Guinea-Pig And Rat Airways

Rationale: Deshpande et al. (Nat Med 2010) reported that several bitter taste receptor (TAS2R) agonists evoked relaxation of mice and human airways. We examined the effects of three prototype agonists in segments of guinea pig trachea (GPT). Methods: GPT was pre-contracted with 0.1 μM carbachol in both absence and presence of 3 μM indomethacin or prostaglandin antagonists. The segments were either exposed to denatonium, chloroquine or saccharin, or kept untreated. Expression of TAS2Rs in guinea pig tracheal epithelium and smooth muscle was measured with real-time PCR. Results: Denatonium and chloroquine induced concentration-dependent relaxations whereas saccharin had no effect. In consistency with these findings, there was expression of TAS2R4 and TAS2R10 for denatonium, and TAS2R3 and TAS2R10 for chloroquine, but not of TAS2Rs for saccharin in guinea pig airways. Denatonium was 6.1-fold more potent than chloroquine (pEC 50 4.7±0.1 and 3.8±0.1, respectively). Indomethacin had no effects on the potency of denatonium and chloroquine. However, the magnitude of the denatonium-induced relaxation (57.5±5.2%; n=8) was enhanced by indomethacin (97.7±2.3%; n=8) and the prostaglandin E 2 receptor (EP 1 ) antagonist ONO-8310 (99.3±0.7; n=5). Chloroquine induced almost complete relaxation (98.2±1.1%; n=6) that was unaffected by indomethacin (99.9±0.04%; n=7). Conclusion: Denatonium and chloroquine induced relaxation of GPT and their respective TAS2Rs were expressed. There was an interaction between denatonium and PGE 2 acting on EP 1 receptors. The findings support the concept that airway TAS2Rs represent a novel target for anti-asthmatic therapy.