title: Comparison of receptor binding characteristics of commonly used muscarinic antagonists in human bladder detrusor and mucosa.
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 M(2)/M(4) receptors. There was an excellent correlation (r(2) = 0.99) of low-affinity global estimates between detrusor and mucosa, whereas the corresponding high-affinity estimates ( approximately 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.
authors.affiliation: Department of Pharmacology, School of Medical Sciences, University of New South Wales, Sydney, New South Wales, Australia. kylie_mansfield@uow.edu.au
authors.forename: Kylie J
authors.initials: KJ
authors.lastname: Mansfield
authors.forename: Jonathan J
authors.initials: JJ
authors.lastname: Chandran
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Vaux
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Millard
authors.forename: Arthur
authors.initials: A
authors.lastname: Christopoulos
authors.forename: Frederick J
authors.initials: FJ
authors.lastname: Mitchelson
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Burcher
mesh_terms: D000368:Aged; D001559:Benzhydryl Compounds / Q000494:pharmacology; D001572:Benzofurans / Q000494:pharmacology; D003408:Cresols / Q000494:pharmacology; D015653:Cystectomy; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009092:Mucous Membrane / Q000378:metabolism*; D018727:Muscarinic Antagonists / Q000494:pharmacology*; D010665:Phenylpropanolamine / Q000494:pharmacology; D011468:Prostatectomy; D011759:Pyrrolidines / Q000494:pharmacology; D011812:Quinuclidines / Q000494:pharmacology; D011813:Quinuclidinyl Benzilate / Q000378:metabolism; D011869:Radioligand Assay; D011976:Receptors, Muscarinic / Q000378:metabolism*; D000069464:Solifenacin Succinate; D044005:Tetrahydroisoquinolines / Q000494:pharmacology; D000068737:Tolterodine Tartrate; D001743:Urinary Bladder / Q000378:metabolism*; D053201:Urinary Bladder, Overactive / Q000378:metabolism*
chemical_list: D001559:Benzhydryl Compounds; D001572:Benzofurans; D003408:Cresols; D018727:Muscarinic Antagonists; D011759:Pyrrolidines; D011812:Quinuclidines; D011976:Receptors, Muscarinic; D044005:Tetrahydroisoquinolines; D010665:Phenylpropanolamine; D000068737:Tolterodine Tartrate; C526675:fesoterodine; D011813:Quinuclidinyl Benzilate; C101207:darifenacin; D000069464:Solifenacin Succinate