부산대학교 도서관

To purchase or authenticate to the full-text of this article, please visit this link: http://dx.doi.org/10.1111/j.1365-2125.2008.03194.x Byline: Teresa M. Attina, James J. Oliver (1), Lorenzo S. Malatino (2), David J. Webb Keywords: acetylcholine; atropine; darifenacin; forearm blood flow; muscarinic receptors Abstract: WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT * Available evidence suggests that the M.sub.3 receptor on endothelial cells is responsible for acetylcholine (Ach)-dependent vasodilatation. * Data from human studies only provide indirect evidence for this, and results are more difficult to interpret. WHAT THIS STUDY ADDS * This study used the new M.sub.3 receptor antagonist darifenacin as a pharmacological 'tool' to investigate the role of M.sub.3 receptor in the human forearm circulation. * It provides evidence for a major role for the M.sub.3 receptors in ACh-dependent vasodilatation in the forearm vascular bed. AIMS 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.sub.3 receptors. Darifenacin is a recently developed antimuscarinic drug with greater M.sub.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 vasoditation 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 [micro]g min.sup.-1 {mean difference from placebo 5.8 [95% confidence interval (CI) 3.1, 8.7] ml min.sup.-1 per 100 ml of forearm volume, P < 0.001} and to ACh 60 [micro]g min.sup.-1[mean difference from placebo 5.9 (95% CI 3.1, 8.7) ml min.sup.-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.sub.3 receptors play a major role in ACh-induced endothelium-mediated vasodilatation. Author Affiliation: (1)Department of Cardiology, The Royal Hallamshire Hospital, Sheffield, UK, and (2)Unit of Internal Medicine and Hypertension Centre, Teaching Hospital of Ragusa, University of Catania, Italy Article History: Received4 January 2008Accepted1 April 2008Published OnlineEarly16 May 2008 Article note: Professor David Webb, Clinical Pharmacology Unit, University of Edinburgh, Queen's Medical Research Institute, 3rd Floor East Room E3.22, 47 Little France Crescent, Edinburgh EH16 4TJ, Scotland, UK., Tel: + 44 131 242 9215, Fax: + 44 870 134 0897, E-mail: d.j.webb@ed.ac.uk