title: Contribution of the M3 muscarinic receptors to the vasodilator response to acetylcholine in the human forearm vascular bed.
abstract: OBJECTIVE
  Acetylcholine (ACh) is a muscarinic agonist that causes receptor-mediated, endothelium-dependent vasodilatation in the forearm vasculature. Previous indirect evidence suggests this effect may be mediated by muscarinic M(3) receptors. Darifenacin is a recently developed antimuscarinic drug with greater M(3) selectivity, and our main objective was to investigate whether darifenacin affects dose-dependent vasodilatation to ACh in the forearm circulation.
  
  
  METHODS
  Healthy subjects were enrolled in two studies designed to assess the effects of atropine and darifenacin on the forearm blood flow (FBF) response to ACh.
  
  
  RESULTS
  In both studies ACh caused similar dose-dependent vasodilation in the forearm vasculature. In study I (5 subjects), the FBF response to ACh was largely attenuated by pretreatment with the nonselective muscarinic antagonist atropine. In study II (10 subjects), oral administration of darifenacin 15 mg for 1 week significantly reduced the FBF dose-dependent response to ACh 20 microg min(-1) (mean difference from placebo 5.8 [95% confidence interval (CI) 3.1, 8.7] ml min(-1) per 100 ml of forearm volume, P < 0.001) and to ACh 60 microg min(-1)[mean difference from placebo 5.9 (95% CI 3.1, 8.7) ml min(-1) per 100 ml of forearm volume, P < 0.001]. After darifenacin, the AUC of change in FBF from baseline was reduced by almost 50% compared with placebo.
  
  
  CONCLUSIONS
  These results suggest that, in the forearm vasculature, muscarinic M(3) receptors play a major role in ACh-induced endothelium-mediated vasodilatation.
authors.affiliation: Clinical Pharmacology Unit, Centre for Cardiovascular Science, Queen's edical Research Institute, University of Edinburgh, Edinburgh, Scottland, UK.
authors.forename: Teresa M
authors.initials: TM
authors.lastname: Attinà
authors.forename: James J
authors.initials: JJ
authors.lastname: Oliver
authors.forename: Lorenzo S
authors.initials: LS
authors.lastname: Malatino
authors.forename: David J
authors.initials: DJ
authors.lastname: Webb
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology*; D000328:Adult; D016022:Case-Control Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004730:Endothelium, Vascular / Q000187:drug effects*; D005260:Female; D005542:Forearm / Q000098:blood supply* / Q000503:physiopathology; D006801:Humans; D008297:Male; D011976:Receptors, Muscarinic / Q000187:drug effects*; D014655:Vascular Resistance / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: D011976:Receptors, Muscarinic; D014665:Vasodilator Agents; D000109:Acetylcholine