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Bitter taste receptor agonists mediate relaxation of human and rodent vascular smooth muscle.

Manson, Martijn L; Säfholm, Jesper; Al-Ameri, Mamdoh; Bergman, Per; Orre, Ann-Charlotte; Swärd, Karl LU ; James, Anna; Dahlén, Sven-Erik and Adner, Mikael LU (2014) In European Journal of Pharmacology 740(Jul 15). p.302-311
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,... (More)
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 Ca(2+) 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. (Less)
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organization
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type
Contribution to journal
publication status
published
subject
in
European Journal of Pharmacology
volume
740
issue
Jul 15
pages
302 - 311
publisher
Elsevier
external identifiers
  • pmid:25036266
  • wos:000341163700038
  • scopus:84906055476
ISSN
1879-0712
DOI
10.1016/j.ejphar.2014.07.005
language
English
LU publication?
yes
id
bb37bd57-c8d6-4518-8ce0-8d32e03a1d19 (old id 4581975)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/25036266?dopt=Abstract
date added to LUP
2014-08-08 17:33:28
date last changed
2017-11-12 03:08:09
@article{bb37bd57-c8d6-4518-8ce0-8d32e03a1d19,
  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 Ca(2+) 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.},
  author       = {Manson, Martijn L and Säfholm, Jesper and Al-Ameri, Mamdoh and Bergman, Per and Orre, Ann-Charlotte and Swärd, Karl and James, Anna and Dahlén, Sven-Erik and Adner, Mikael},
  issn         = {1879-0712},
  language     = {eng},
  number       = {Jul 15},
  pages        = {302--311},
  publisher    = {Elsevier},
  series       = {European Journal of Pharmacology},
  title        = {Bitter taste receptor agonists mediate relaxation of human and rodent vascular smooth muscle.},
  url          = {http://dx.doi.org/10.1016/j.ejphar.2014.07.005},
  volume       = {740},
  year         = {2014},
}