Demonstration of Muscarinic and Nicotinic Receptor Binding Activities of Distigmine to Treat Detrusor Underactivity

• Harada Taketsugu

  Department of Pharmacokinetics and Pharmacodynamics and Global Center of Excellence (COE) Program, School of Pharmaceutical Sciences, University of Shizuoka

• Fushimi Kazumi

  Department of Pharmacokinetics and Pharmacodynamics and Global Center of Excellence (COE) Program, School of Pharmaceutical Sciences, University of Shizuoka

• Kato Aya

  Department of Pharmacokinetics and Pharmacodynamics and Global Center of Excellence (COE) Program, School of Pharmaceutical Sciences, University of Shizuoka

• Ito Yoshihiko

  Department of Pharmacokinetics and Pharmacodynamics and Global Center of Excellence (COE) Program, School of Pharmaceutical Sciences, University of Shizuoka

• Nishijima Saori

  Southern Knights' Laboratory LLP

• Sugaya Kimio

  Southern Knights' Laboratory LLP

• Yamada Shizuo

  Department of Pharmacokinetics and Pharmacodynamics and Global Center of Excellence (COE) Program, School of Pharmaceutical Sciences, University of Shizuoka

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-³H]scopolamine methyl chloride ([³H]NMS ) and [³H]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 [³H]oxotremorine-M compared with those of [³H]NMS as revealed by large ratios of its K_i value for [³H]NMS to that for [³H]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 [³H]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.

Journal

• Biological and Pharmaceutical Bulletin

  Biological and Pharmaceutical Bulletin 33 (4), 653-658, 2010

  The Pharmaceutical Society of Japan

Keywords

• detrusor underactivity
• distigmine
• muscarinic receptor
• nicotinic receptor

Details

• CRID: 1390282679604867840
• NII Article ID: 130000248014
• NII Book ID: AA10885497
• DOI: 10.1248/bpb.33.653
• ISSN: 13475215
• ISSN: 09186158
• NDL BIB ID: 10622769
• Web Site: http://id.ndl.go.jp/bib/10622769
• Web Site: https://ndlsearch.ndl.go.jp/books/R000000004-I10622769
• Web Site: http://www.jstage.jst.go.jp/article/bpb/33/4/33_4_653/_pdf
• Web Site: https://search.jamas.or.jp/link/ui/2010223463
• Text Lang: en
• Data Source:
  • JaLC
  • NDL
  • Crossref
  • CiNii Articles
• Abstract License Flag: Disallowed