| Co-Investigator(Kenkyū-buntansha) |
TAKATORI Yuki Doshisha Women's College of Liberal Arts, Faculty of Pharmaceutical Sciences, Research Associate (90411090)
YAMADA Shizuo University of Shizuoka, Faculty of Pharmaceutical Sciences, Professor (80106434)
TAKEUCHI Tadayoshi Osaka Prefecture University, Grad Sch Life Env Sci, Professor (00171611)
MATSUI Minoru Chiba Institute of Science, Faculty of Pharmacy, Associate Professor (50282611)
KAWASHIMA Koichiro Musashino University, Faculty of Pharmacy, Visiting Professor (70095008)
|
|---|
| Research Abstract |
Muscarinic acetylcholine receptor (mAChR) knockout (KO) mice, which were developed and supplied by Dr Matsui (Chiba Institute of Science), were used. Regulation of Immunological response: On the 14th day after immunization, serum antigen specific IgG_1 levels in M_1/M5-KO mice were significantly lower than those of wild-type mice. In addition, concanavalin A-induced ChAT, an ACh-synthesizing enzyme, interleukin-2 and c-fos mRNA expression in wild-type mice. These gene expressions were significantly reduced, in M_3 KO-mice, when compared with those of wild-type mice. These findings suggested that M_1/M_5 and M_3 mAChR may involved in regulation of lymphocyte function. Relaxation of Urinary bladder muscle: In wild-type mice, carbachol (CCh) relaxed noradrenaline-induced contraction in a dose-dependent manner. However, relaxation by CCh was decreased in M_3-KO mice, but not changed in M_2-KO mice. In addition, CCh-induced response was antagonized by indomethacin. In addition, PGE_2 induce
… More
d concentration dependent relaxation. These findings suggest that M_3 mAChR and PGE_2 are involved in relaxation of urinary bladder muscle. Changes in mAChR ligand properties: Characterization of mAChR binding activity in the bladder and submandibular gland after oral administration of oxybutynin (Oxy) and solifenacin (Sol) to M_2-KO mice was performed. There was little difference between bladder and submandibular gland of M_2-KO mice in in vitro mAChR binding activities of Oxy and Sol, suggesting equal affinity to the residual (predominantly M_3) mAChR in both tissues. In contrast, compared with that after oral Oxy, oral Sol exerted significantly greater binding activity to the bladder mAChR of M_2-KO mice, whereas oral Sol exhibited significantly smaller binding activity to the exocrine gland mAChR. These data indicate that oral Sol, unlikely oral, may exert greater binding to M_3 mAChR of bladder than exocrine gland under in vivo condition. Oral Sol may be advantageous for the treatment of overactive bladder, in terms of high selectivity to bladder. Less
|
