200 THE EFFECT OF KNOCK OUT OF UROTHELIAL M 3 RECEPTORS ON MOUSE BLADDER CONTRACTILITY

Abstract

You have accessJournal of UrologyBladder and Urethra: Anatomy, Physiology and Pharmacology I1 Apr 2010200 THE EFFECT OF KNOCK OUT OF UROTHELIAL M3 RECEPTORS ON MOUSE BLADDER CONTRACTILITY Alan Braverman, Yael Kreitman, and Michael Ruggieri Alan BravermanAlan Braverman More articles by this author , Yael KreitmanYael Kreitman More articles by this author , and Michael RuggieriMichael Ruggieri More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2010.02.256AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Our previous studies demonstrate that outlet obstruction in the rat results in increased urothelial muscarinic receptors density. Urothelial muscarinic receptors activate calcium transients and modulate ATP and NO release which may act on afferent nerves to alter voiding frequency. The aim of the present study was to determine the effect of urothelial-specific M3 knock out on bladder contractility. METHODS Urothelial specific M3 KO mice were developed by breeding floxed M3 receptor mice with mice expressing cre-recombinase downstream from the uroplakin II promoter. Cumulative carbachol concentration effect curves were generated with and without darifenacin. In-vivo cystometry was performed with vehicle or antagonist infused at a rate of 1 ml/h through a suprapubic tube. RESULTS There is no difference between urothelium intact wild type (n=14) and uroM3 KO (n=6) bladder strips in the carbachol maximal or the KCl induced contraction. However, carbachol potency is significantly greater (p<0.05) in urothelium intact uroM3 KO than in wild type bladder strips (0.99 vs. 3.6 μM respectively at the 30% of KCl effect level). Carbachol potency is reduced following urothelium removal from uroM3 KO animals, but not wild type bladders. The M3 selective antagonist darifenacin is highly potent (pKb=9.2) in urothelium intact uroM3 KO mice bladder strips, consistent with M3 receptors mediating contraction (Figure 1). Darifenacin is not as potent in attenuating the maximal contraction with the urothelium removed. Micturition pressure is higher in uroM3 KO animals (33±10 cmH20) than in wild type animals (24±7 cmH20) but this difference is not statistically significant. 4-DAMP is significantly more potent (p<0.05) in reducing micturition pressure in wild type than uroM3 KO animals (Figure 2). CONCLUSIONS Urothelial muscarinic receptors modulate bladder contractility. Urothelial M3 receptors may mediate a negative feedback that reduces carbachol potency in-vitro and possibly micturition pressure in-vivo. Philadelphia, PA© 2010 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 183Issue 4SApril 2010Page: e79 Advertisement Copyright & Permissions© 2010 by American Urological Association Education and Research, Inc.MetricsAuthor Information Alan Braverman More articles by this author Yael Kreitman More articles by this author Michael Ruggieri More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...