title: Demonstration of muscarinic and nicotinic receptor binding activities of distigmine to treat detrusor underactivity.
abstract: The present study was undertaken to examine whether distigmine, a therapeutic agent used to treat detrusor underactivity, binds directly to muscarinic and nicotinic receptors. We used radioreceptor binding assays and compared the effects of distigmine with those of neostigmine and donepedil. The inhibitory effect of distigmine on the blood acetylcholinesterase (AChE) activity was significantly weaker than that of neostigmine. Distigmine, neostigmine, and donepezil competed for specific binding sites of [N-methyl-(3)H]scopolamine methyl chloride ([(3)H]NMS ) and [(3)H]oxotremorine-M in the bladder, submaxillary gland and cerebral cortex of rats in a concentration-dependent manner, indicating significant binding activity of muscarinic receptors. Distigmine displayed significantly higher affinity for binding sites of [(3)H]oxotremorine-M compared with those of [(3)H]NMS as revealed by large ratios of its K(i) value for [(3)H]NMS to that for [(3)H]oxotremorine-M, suggesting that it has preferential affinity for agonist sites of muscarinic receptors. Distigmine seemed to bind to the agonist sites of muscarinic receptors in a competitive manner. Repeated oral administration of distigmine caused a significant decrease in the maximal number of binding sites (B(max)) for [(3)H]NMS in the bladder and submaxillary gland but not cerebral cortex. Distigmine also bound to nicotinic receptors in the rat cerebral cortex. In conclusion, distigmine shows direct binding to muscarinic receptors in the rat bladder, and repeated oral administration of distigmine causes downregulation of muscarinic receptors in the rat bladder. The observed direct interaction of distigmine with the bladder muscarinic receptors may partly contribute to the therapeutic and/or side effects seen in the treatment of detrusor underactivity.
authors.affiliation: Department of Pharmacokinetics and Pharmacodynamics and Global Center of Excellence (COE) Program, School of Pharmaceutical Sciences, University of Shizuoka, USA.
authors.forename: Taketsugu
authors.initials: T
authors.lastname: Harada
authors.forename: Kazumi
authors.initials: K
authors.lastname: Fushimi
authors.forename: Aya
authors.initials: A
authors.lastname: Kato
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Ito
authors.forename: Saori
authors.initials: S
authors.lastname: Nishijima
authors.forename: Kimio
authors.initials: K
authors.lastname: Sugaya
authors.forename: Shizuo
authors.initials: S
authors.lastname: Yamada
mesh_terms: D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D002540:Cerebral Cortex / Q000187:drug effects; D002800:Cholinesterase Inhibitors / Q000378:metabolism* / Q000627:therapeutic use; D015536:Down-Regulation; D008297:Male; D018721:Muscarinic Agonists / Q000494:pharmacology* / Q000627:therapeutic use; D009130:Muscle, Smooth / Q000187:drug effects*; D010095:Oxotremorine / Q000031:analogs & derivatives; D011726:Pyridinium Compounds / Q000378:metabolism* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D011976:Receptors, Muscarinic / Q000737:chemistry / Q000378:metabolism*; D011978:Receptors, Nicotinic / Q000737:chemistry / Q000378:metabolism; D012601:Scopolamine; D013363:Submandibular Gland / Q000187:drug effects; D001743:Urinary Bladder / Q000187:drug effects* / Q000378:metabolism; D001745:Urinary Bladder Diseases / Q000188:drug therapy* / Q000378:metabolism
chemical_list: D002800:Cholinesterase Inhibitors; D018721:Muscarinic Agonists; D011726:Pyridinium Compounds; D011976:Receptors, Muscarinic; D011978:Receptors, Nicotinic; D010095:Oxotremorine; C042743:oxotremorine M; D012601:Scopolamine; C084645:distigmine