Contribution of the M3 muscarinic receptors to the vasodilator response to acetylcholine in the human forearm vascular bed

Abstract

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 M3 receptors. Darifenacin is a recently developed antimuscarinic drug with greater M3 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 M3 receptors play a major role in ACh-induced endothelium-mediated vasodilatation. © 2008 The Authors.