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First published on November 24, 2008; DOI: 10.1124/jpet.108.145508
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Received for publication September 23, 2008.
Revised November 16, 2008.
Accepted for publication November 17, 2008.

Comparison of receptor binding characteristics of commonly used muscarinic antagonists in human bladder detrusor and mucosa

Kylie J Mansfield 1*, Jonathan J Chandran 2, Kenneth J Vaux 3, Richard J Millard 4, Arthur Christopoulos 5, Fredrick J Mitchelson 6, Elizabeth Burcher 2

1 University of Wollongong 2 University of New South Wales 3 Sydney Adventist Hospital 4 Prince of Wales Hospital 5 Monash University 6 University of Melbourne

* Address correspondence to: E-mail: kylie{at}uow.edu.au

Abstract

Recent studies have described muscarinic receptors on the mucosa as well as the detrusor of the human urinary bladder. Muscarinic receptor antagonists are effective in the treatment of overactive bladder (OAB), but their site(s) of action and actual therapeutic target are unclear. Our aim was to compare, in human bladder mucosa and detrusor, the radioligand binding characteristics of newer, clinically effective agents: darifenacin, its hydroxylated metabolite UK-148,993, fesoterodine, solifenacin, tolterodine and trospium. Specimens were collected from asymptomatic patients (aged 50-72years) undergoing open bladder surgery. Radioligand binding studies with the muscarinic antagonist [3H]quinuclidinyl benzilate (QNB) were performed separately on detrusor and mucosal membranes. All antagonists displayed high affinity when competing for [3H]QNB binding in both detrusor and mucosa. Inhibition constants were also obtained for all antagonists against individual muscarinic receptor subtypes expressed in CHO cells. Here, fesoterodine showed anomalous binding results, suggesting that some conversion to its metabolite had occurred. Global nonlinear regression analysis of bladder binding data with five antagonists demonstrated 82% low affinity sites in mucosa and 78% low affinity sites in detrusor, probably representing M2/M4 receptors. There was an excellent correlation (r2=0.99) of low affinity global estimates between detrusor and mucosa, whereas the corresponding high affinity estimates ({approx}20% of sites) were dissimilar. In conclusion, commonly used and clinically effective muscarinic receptor antagonists bind to receptors located on the bladder mucosa as well as the detrusor, providing support for the hypothesis that muscarinic receptors in the mucosa may represent an important site of action for these agents in OAB.


Key words: 3[H]QNB, detrusor, human, muscarinic receptors, urinary bladder, urothelium




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