Comparison of Receptor Binding Characteristics of Commonly Used Muscarinic Antagonists in Human Bladder Detrusor and Mucosa
- Kylie J. Mansfield,
- Jonathan J. Chandran,
- Kenneth J. Vaux,
- Richard J. Millard,
- Arthur Christopoulos,
- Frederick J. Mitchelson and
- Elizabeth Burcher
- Department of Pharmacology, School of Medical Sciences, University of New South Wales, Sydney, New South Wales, Australia (K.J.M., J.J.C., E.B.); Graduate School of Medicine, University of Wollongong, Wollongong, New South Wales, Australia (K.J.M.); Sydney Adventist Hospital, Woollahra, New South Wales, Australia (K.J.V.); Department of Urology, Prince of Wales Hospital, Randwick, New South Wales, Australia (R.J.M.); Drug Discovery Biology Laboratory, Monash Institute of Pharmaceutical Sciences & Department of Pharmacology, Monash University, Victoria, Australia (A.C.); and Department of Pharmacology, University of Melbourne, Parkville, Victoria, Australia (F.J.M.)
- Address correspondence to:
Dr. Kylie Mansfield, Graduate School of Medicine, University of Wollongong, Wollongong, NSW 2522, Australia. E-mail: kylie_mansfield{at}uow.edu.au
Abstract
Recent studies have described muscarinic receptors on the mucosa and 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 (50-72 years old) 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 Chinese hamster ovary 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 (∼20% of sites) were dissimilar. In conclusion, commonly used and clinically effective muscarinic receptor antagonists bind to receptors located on the bladder mucosa and 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.
Footnotes
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This work was supported by the Faculty of Medicine, University of New South Wales and by Dr. R. Pfleger GmbH (Bamberg, Germany).
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doi:10.1124/jpet.108.145508.
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ABBREVIATIONS: OAB, overactive bladder; UK-148,993, hydroxylated metabolite of darifenacin; SPM7605, active metabolite of fesoterodine and tolterodine; [3H]QNB, [3H]quinuclidinyl benzilate; CHO, Chinese hamster ovary.
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- Received September 22, 2008.
- Accepted November 17, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
