Molecular mechanisms underlying age-dependent decrease of water transport in salivary glands and the investigation of the drug in xerostomia

年龄依赖性唾液腺水分运输减少的分子机制及药物治疗口干症的研究

• 批准号: 11557137
• 负责人: ISHIKAWA Yasuko
• 金额: $ 8.58万
• 依托单位: The University of Tokushima
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-11557137/
• 关键词: Water channel; Aquaporin-5; cis-2-methylspiro-(1,3-oxathiolane-5, 3')-quinuclidine; Aging; Salivary glands; [ Ca^<2+> ]i; M3-Muscarinic receptor; Apical plasma membrane; 糖輸送体; M_3スカリン受容体

The stimulatory effect of acetylcholine, but not that of epinephrine, on the abundance of aquaporin-5 in the apical plasma membrane (APM) of parotid acinar cells was markedly reduced in tissue from senescent rats relative to that in tissue from young adult animals. In this study, we looked for the drug which persistent increase in the amount AQP5 in the APM of-parotid glands of senescent rats.cis-2-methylspiro-(1,3-oxathiolane-5,3')-quinuclidine induced a marked increase of AQP5 in the APM of parotid tissues in a dose-dependent manner with an EC_<50> value of 14.2 ± 2.3 nM. cis-2-methylspiro-(1,3-oxathiolane-5,3')-quinuclidine- and pilocarpine-induced increase in the amount of AQP5 in the APM was maximal at 10 and 3 min, respectively, and persisted for longer than 30 min. This increase was inhibited by pF-HHSiD, U73122, dantrolene or TMB-8, but not by GF 109203X. In the presence of extracellular CaCl_2, cis-2-methylspiro- (1,3- oxathiolane-5,3')-quinuclidine induced marked and persistent oscillations in [ Ca^<2+> ]i in isolated acinar cells. These results suggest that cis-2-methylspiro-(1,3- oxathiolane-5,3')-quinuclidine acts at M_3 receptors to induce a persistent increase in the amount of AQP5 in APM of parotid acini, and that this effect is mediated by the release of Ca^<2+> from intracellular stores through both inositol 1,4,5-trisphosphate and ryanodine receptors.The cis-2-methylspiro-(1,3-oxathiolane-5,3')-quinuclidine induced a persistent increase in the amount of aquaporin-5 in the apical plasma membrane that was similar for parotid tissue from young adult and senescent rats, suggesting that this drug prove effective for treatment of age-related xerostomia.

乙酰胆碱的刺激作用，但不是肾上腺素，水通道蛋白-5的丰度在腮腺腺泡细胞的顶端质膜（APM）的显着减少，在组织中相对于年轻的成年动物的组织从衰老大鼠。本研究寻找一种能持续增加衰老大鼠腮腺APM中AQP 5含量的药物，顺-2-甲基螺-（1，3-氧硫杂环戊烷-5，3 '）-奎宁环能剂量依赖性地诱导衰老大鼠腮腺APM中AQP 5含量的增加，其EC<50>值为14.2 ± 2.3nM。cis-2-methylspiro-（1，3-oxathiolane-5，3 '）-quinuclidine-和pilocarpine-诱导的APM中AQP 5的量的增加分别在10和3 min时达到最大，并持续超过30 min。pF-HHSiD、U 73122、dantrolene或TMB-8抑制这种增加，但GF 109203 X不抑制这种增加。在细胞外CaCl_2存在的情况下，cis-2-methylspiro-（1，3- oxathiolane-5，3 '）-quinuclidine可引起离体腺泡细胞[ Ca^&lt;2+&gt; ]i的显著和持续的振荡。这些结果表明，顺式-2-甲基螺-（1，3-氧硫杂环戊烷-5，3 '）-奎宁环作用于M_3受体，诱导腮腺腺泡APM中AQP 5含量持续增加，该作用是通过1，4，5-三磷酸肌醇和兰尼定受体从细胞内储存释放Ca^&lt;2+&gt;介导的。顺式-2-甲基螺环-（1，3-氧硫杂环戊烷-5，3 '）-奎宁环诱导顶端质膜中水通道蛋白-5的量的持续增加，这与来自年轻成年大鼠和衰老大鼠的腮腺组织相似，表明该药物证明对治疗年龄相关性口干症有效。

项目成果

Yasuko Ishikawa: "SNI-2011 acts on M3-receptors and induces the long-lasting increase in the amount of aquaporin-5 in the apical plasma membrane of rat parotid glands"The Japanese Journal of Pharmacology. 79 Suppl.I. 92 (1999)

Yasuko Ishikawa：“SNI-2011 作用于 M3 受体，诱导大鼠腮腺顶端质膜中水通道蛋白 5 含量的持久增加”《日本药理学杂志》。

Mariusz T.: "Enhancement by epinephrine of benzylpenicillin transport in rat small intestine."The Journal of Pharmacology and Experimental Therapeutics. 293・1(in press). (2000)

Mariusz T.：“肾上腺素增强大鼠小肠中的青霉素转运”，《药理学和实验治疗学杂志》293·1（出版中）。

井上紀子: "糖尿病と唾液腺分泌機能の変化"歯科基礎医学会雑誌. Vol.43, No.5. 588 (2001)

井上纪子：“糖尿病和唾液腺分泌功能的变化”日本基础牙科医学会杂志第43卷，第588期（2001年）。

Yasuko Ishikawa: "「Molecular biology and physiology of water and solute transport」 Edited by Stefan"Kluwer Academic/Plenum Publishers, London, UK. 451 (2001)

Yasuko Ishikawa：“水和溶质运输的分子生物学和生理学”，Stefan 编辑”Kluwer Academy/Plenum Publishers，伦敦，英国。451（2001）

Yasuko Ishikawa: "Activation of endogenous nitric oxide synthase coupled with methacholine-induced exocytosis in rat parotid acinar cells"J. Pharmacol. Exp. Ther.. Vol.301 No.1. 1-9 (2002)

Yasuko Ishikawa：“内源性一氧化氮合酶的激活与乙酰甲胆碱诱导的大鼠腮腺腺泡细胞的胞吐作用相结合”J。