title: Bitter taste receptor agonists mediate relaxation of human and rodent vascular smooth muscle.
abstract: Taste-sensing type 2 receptors (TAS2Rs) have been implicated in extraoral functions. Airway smooth muscle expresses TAS2Rs and is strongly relaxed by TAS2R agonists. We hypothesised that TAS2R agonists might affect vascular smooth muscle as well. Moreover, the general pharmacological profile of TAS2R agonists, which are used to investigate the functions of TAS2R׳s, are undefined. The aim of this study was to pharmacologically characterise the effects of five prototype TAS2R agonists in vascular smooth muscle. Responses to the TAS2R agonists were investigated in guinea-pig aorta and taenia coli, mouse aorta (wild-type and caveolin-1-/- mice) and human pulmonary arteries. Chloroquine, denatonium, dextromethorphan, noscapine and quinine, agonists for TAS2R3, TAS2R4, TAS2R10 and TAS2R14, induced strong endothelium-independent relaxations (responses between 82-96% of maximal relaxations) in phenylephrine pre-contracted guinea-pig aorta that persisted in the presence of L-type Ca2+ and KCa1.1-channel blockers. Experiments in guinea-pig taenia coli revealed that denatonium and quinine also inhibited relaxations to phenylephrine, indicating antagonism of α-adrenoceptors. Only chloroquine and noscapine mediated relaxations when the guinea pig aorta was pre-contracted by U-46619 or PGF2α. Relaxations to chloroquine and noscapine after U-46619 pre-contractions were however markedly impaired in aortae from caveolin-1-/- mice. Chloroquine and noscapine mediated relaxations of human pulmonary arteries that expressed also mRNA for TAS2R3, TAS2R4, TAS2R10 and TAS2R14, at levels similar to that of the α1A adrenoceptor. Notwithstanding whether TAS2Rs are involved or not, TAS2R agonists have profound effects on vascular smooth muscle. Chloroquine and noscapine are of special interest as their effects cannot be accounted for by conventional pathways.
authors.affiliation: Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden. Electronic address: martijn.manson@ki.se.
authors.forename: Martijn L
authors.initials: ML
authors.lastname: Manson
authors.affiliation: Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Jesper
authors.initials: J
authors.lastname: Säfholm
authors.affiliation: Department of Molecular Medicine and Surgery (MMK), Karolinska Institutet, Stockholm, Sweden; Department of Cardiothoracic Surgery and Anesthesiology, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Mamdoh
authors.initials: M
authors.lastname: Al-Ameri
authors.affiliation: Department of Molecular Medicine and Surgery (MMK), Karolinska Institutet, Stockholm, Sweden; Department of Cardiothoracic Surgery and Anesthesiology, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Per
authors.initials: P
authors.lastname: Bergman
authors.affiliation: Department of Molecular Medicine and Surgery (MMK), Karolinska Institutet, Stockholm, Sweden; Department of Cardiothoracic Surgery and Anesthesiology, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Ann-Charlotte
authors.initials: AC
authors.lastname: Orre
authors.affiliation: Department of Experimental Medical Science, Lund University, Lund, Sweden.
authors.forename: Karl
authors.initials: K
authors.lastname: Swärd
authors.affiliation: Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: James
authors.affiliation: Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Sven-Erik
authors.initials: SE
authors.lastname: Dahlén
authors.affiliation: Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Mikael
authors.initials: M
authors.lastname: Adner
mesh_terms: D000368:Aged; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects* / Q000502:physiology; D002738:Chloroquine / Q000494:pharmacology; D003106:Colon / Q000187:drug effects* / Q000502:physiology; D003915:Dextromethorphan / Q000494:pharmacology; D005260:Female; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000502:physiology; D009665:Noscapine / Q000494:pharmacology; D011651:Pulmonary Artery / Q000187:drug effects* / Q000502:physiology; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology; D011803:Quinine / Q000494:pharmacology; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000502:physiology; D012439:Saccharin / Q000494:pharmacology; D013649:Taste; D014132:Trachea / Q000187:drug effects* / Q000502:physiology
chemical_list: D002738:Chloroquine; D003915:Dextromethorphan; D009665:Noscapine; D000644:Quaternary Ammonium Compounds; D011803:Quinine; D043562:Receptors, G-Protein-Coupled; D012439:Saccharin; C043414:denatonium
keywords: Airway smooth muscle; Human pulmonary artery; TP receptor; Taste physiology; Taste-sensing type 2 receptors (TAS2Rs); Vascular smooth muscle