PT  - JOURNAL ARTICLE
AU  - Ville Pulkkinen
AU  - Jesper Säfholm
AU  - Martijn Manson
AU  - Mikael Adner
AU  - Sven-Erik Dahlén
TI  - Bitter taste receptor agonists as a novel class of bronchodilators in guinea-pig airways
DP  - 2011 Sep 01
TA  - European Respiratory Journal
PG  - 4683
VI  - 38
IP  - Suppl 55
4099  - http://erj.ersjournals.com/content/38/Suppl_55/4683.short
4100  - http://erj.ersjournals.com/content/38/Suppl_55/4683.full
SO  - Eur Respir J2011 Sep 01; 38
AB  - 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 (pEC50 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 E2 receptor (EP1) 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 PGE2 acting on EP1 receptors. The findings support the concept that airway TAS2Rs represent a novel target for anti-asthmatic therapy.