Cardiovascular pharmacology Bitter taste receptor agonists mediate relaxation of human and rodent vascular smooth muscle Martijn L. Manson a,b,n , Jesper Säfholm a,b , Mamdoh Al-Ameri c,d , Per Bergman c,d , Ann-Charlotte Orre c,d , Karl Swärd e , Anna James a,b , Sven-Erik Dahlén a,b , Mikael Adner a,b a Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden b Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden c Department of Molecular Medicine and Surgery (MMK), Karolinska Institutet, Stockholm, Sweden d Department of Cardiothoracic Surgery and Anesthesiology, Karolinska University Hospital, Stockholm, Sweden e Department of Experimental Medical Science, Lund University, Lund, Sweden article info Article history: Received 14 February 2014 Received in revised form 3 July 2014 Accepted 4 July 2014 Available online 15 July 2014 Keywords: Taste-sensing type 2 receptors (TAS2Rs) Vascular smooth muscle Airway smooth muscle Human pulmonary artery TP receptor Taste physiology 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 À/ À 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 Ca 2 þ and K Ca 1.1-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 PGF 2α . Relaxations to chloroquine and noscapine after U-46619 pre-contractions were however markedly impaired in aortae from caveolin-1 À/ À mice. Chloroquine and noscapine mediated relaxations of human pulmonaryarteries that expressed also mRNA for TAS2R3, TAS2R4, TAS2R10 and TAS2R14, at levels similar to that of the α1 A 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. & 2014 Elsevier B.V. All rights reserved. 1. Introduction Bitter taste-sensing type 2 receptors (TAS2Rs) belong to a family of G-protein coupled receptors that mediate gustatory taste perception in the oral cavity. TAS2Rs are unique as they are capable of recognising a broad range of bitter compounds with a relatively low affinity and specificity that prevents us from con- sumption of potentially harmful substances (Meyerhof et al., 2010). Interestingly, the expression and effects of the TAS2Rs is not restricted to the oral cavity. TAS2Rs are expressed in epithelial cells, where they sense and facilitate clearance of chemical irritants and bacteria, like Pseudo- monas Aeruginosa (Lee et al., 2012; Shah et al., 2009). TAS2R agonists inhibited cytokine release from blood leucocytes and their expression showed a strong correlation with the severity of asthma in children (Orsmark-Pietras et al., 2013). Moreover TAS2Rs are expressed on airway smooth muscle (Deshpande et al., 2010), and there is now a strong body of evidence that TAS2R agonists induce profound bronchodilation in human, guinea pig and mouse airways (Deshpande et al., 2010; Contents lists available at ScienceDirect journal homepage: www.elsevier.com/locate/ejphar European Journal of Pharmacology http://dx.doi.org/10.1016/j.ejphar.2014.07.005 0014-2999/& 2014 Elsevier B.V. All rights reserved. Abbreviations: DMSO, Dimethylsulphoxide; HEK, Human embryonic kidney; K Ca 1.1 channel, Large-conductance Ca 2 þ activated potassium channel; KCl, Potas- sium chloride; KH, Krebs–Henseleit; PCR, Polymerase-chain-reaction; PGF 2α , Prostaglandin F 2α ; TAS2R, Taste-sensing type 2 receptor n Correspondence author at: Department of Experimental Asthma and Allergy Research, Institute of Environmental Medicine, Karolinska Institutet, Scheeles väg 1, mailbox 287, SE-171 77 Stockholm, Sweden. Tel.: þ46 707 655 254; fax: þ46 8 300 619. E-mail address: martijn.manson@ki.se (M.L. Manson). European Journal of Pharmacology 740 (2014) 302–311