Article date: August 2008
By: Teresa M. Attinà, James J. Oliver, Lorenzo S. Malatino, David J. Webb, in Volume 66, Issue 2, pages 300-303
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT
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.
DOI: 10.1111/j.1365-2125.2008.03194.x
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