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Contribution of the M 3 muscarinic receptors to the vasodilator response to acetylcholine in the human forearm vascular bed
Author(s) -
Attinà Teresa M.,
Oliver James J.,
Malatino Lorenzo S.,
Webb David J.
Publication year - 2008
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/j.1365-2125.2008.03194.x
Subject(s) - muscarinic acetylcholine receptor , acetylcholine , atropine , endocrinology , vasodilation , medicine , forearm , agonist , muscarinic acetylcholine receptor m3 , chemistry , pharmacology , receptor , anatomy
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Available evidence suggests that the M 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 3 receptor antagonist darifenacin as a pharmacological ‘tool’ to investigate the role of M 3 receptor in the human forearm circulation. • It provides evidence for a major role for the M 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 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 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 µg 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 µg 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.