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

与年轻成年动物的组织相比，衰老大鼠组织中乙酰胆碱（而非肾上腺素）对腮腺腺泡细胞顶端质膜（APM）中水通道蛋白-5丰度的刺激作用显着降低。在本研究中，我们寻找能够持续增加衰老大鼠腮腺APM中AQP5含量的药物。cis-2-甲基螺环-(1,3-氧硫杂环戊烷-5,3')-奎宁环以剂量依赖性方式诱导腮腺组织APM中AQP5显着增加，EC_<50>值为14.2±2.3nM。顺-2-甲基螺环-(1,3-氧硫杂环戊烷-5,3')-奎宁环和毛果芸香碱诱导的APM中AQP5量的增加分别在10和3分钟时达到最大，并持续超过30分钟。这种增加可被 pF-HHSiD、U73122、dantrolene 或 TMB-8 抑制，但不能被 GF 109203X 抑制。在细胞外CaCl_2存在的情况下，cis-2-甲基螺环-(1,3-氧硫杂环戊烷-5,3')-奎宁环在分离的腺泡细胞中诱导[Ca^2>]i显着且持续的振荡。这些结果表明，顺-2-甲基螺环-(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AQP5的量持续增加，并且这种作用是通过肌醇1,4,5-三磷酸和兰尼丁受体从细胞内储存中释放Ca^2来介导的。 cis-2-methylspiro-(1,3-oxathiolane-5,3')-quinuclidine 诱导顶端质膜中水通道蛋白 5 含量的持续增加，这与年轻成年和衰老大鼠的腮腺组织相似，表明该药物可有效治疗与年龄相关的口干症。

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.