title: The bitter taste receptor (TAS2R) agonists denatonium and chloroquine display distinct patterns of relaxation of the guinea pig trachea.
abstract: Activation of taste receptors (TAS2Rs) by bitter taste agonists has been reported to cause bronchodilation. The aim of this study was to extend the information on the effects of bitter taste agonists on responses induced by different contractile mediators in a standard airway physiology preparation. Isometric responses were assessed in guinea pig trachea (GPT). TAS2R agonists were administered either to segments precontracted with different agonists for contraction or given before challenge with the different contractile stimuli, including antigen in tissues from ovalbumin-sensitized animals. TAS2R mRNA expression on GPT epithelium and smooth muscle was measured with real-time PCR. Denatonium, chloroquine, thiamine, and noscapine induced concentration-dependent relaxations (R(max): 98.3 ± 1.6, 100.0 ± 0.0, 100.0 ± 0.0, and 52.3 ± 1.1% of maximum, respectively, in the presence of indomethacin) in segments precontracted with carbachol. The receptors for denatonium (TAS2R4, TAS2R10) and chloroquine (TAS2R3, TAS2R10) were expressed in GPT. Whereas denatonium selectively inhibited contractions induced by carbachol, chloroquine uniformly inhibited contractions evoked by prostaglandin E(2), the thromboxane receptor agonist U-46619, leukotriene D(4), histamine, and antigen. The effects of denatonium, but not those of chloroquine, were partly inhibited by blockers of the large Ca(2+)-activated K(+) channels and decreased by an increase of the level of precontraction. In conclusion, TAS2R agonists mediated strong relaxations and substantial inhibition of contractions in GPT. Chloroquine and denatonium had distinct patterns of activity, indicating different signaling mechanisms. The findings reinforce the hypothesis that TAS2Rs are potential targets for the development of a new class of more efficacious agonists for bronchodilation.
authors.affiliation: The Unit for Asthma and Allergy Research, the National Institute of Environmental Medicine and the Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Ville
authors.initials: V
authors.lastname: Pulkkinen
authors.forename: Martijn L
authors.initials: ML
authors.lastname: Manson
authors.forename: Jesper
authors.initials: J
authors.lastname: Säfholm
authors.forename: Mikael
authors.initials: M
authors.lastname: Adner
authors.forename: Sven-Erik
authors.initials: SE
authors.lastname: Dahlén
mesh_terms: D000420:Albuterol / Q000494:pharmacology; D000818:Animals; D001993:Bronchodilator Agents / Q000494:pharmacology*; D002217:Carbachol / Q000494:pharmacology; D018999:Charybdotoxin / Q000494:pharmacology; D002738:Chloroquine / Q000494:pharmacology*; D018679:Cholinergic Agonists / Q000494:pharmacology; D015870:Gene Expression; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D010455:Peptides / Q000494:pharmacology; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology*; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D020545:Respiratory Mucosa / Q000187:drug effects; D014132:Trachea / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D000098706:Taste Receptors, Type 2
chemical_list: D000420:Albuterol; D001993:Bronchodilator Agents; D002217:Carbachol; D018999:Charybdotoxin; D002738:Chloroquine; D018679:Cholinergic Agonists; D007211:Indoles; D007213:Indomethacin; D051036:Large-Conductance Calcium-Activated Potassium Channels; D010455:Peptides; D000644:Quaternary Ammonium Compounds; D043562:Receptors, G-Protein-Coupled; D000098706:Taste Receptors, Type 2; C048220:paxilline; C064719:iberiotoxin; C043414:denatonium