ROLES OF PHOSPHATIDYLINOSITOL IN THE MECHANISMS INVOLVED IN THE AIRWAY SMOOTH MUSCLE RELAXATION INDUCED BY ATP-SENSITIVE POTASSIUM CHANNEL OPENERS

磷脂酰肌醇在 ATP 敏感钾通道开放剂诱导的气道平滑肌松弛机制中的作用

• 批准号: 08671750
• 负责人: SHIBATA Osamu
• 金额: $ 1.28万
• 依托单位: NAGASAKI UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1996
• 资助国家: 日本
• 起止时间: 1996 至 1997
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-08671750/
• 关键词: phosphatidylinositol; airway smooth muscle; potassium channel opener; Kチャネル; イノシトールリン脂

Since K_<ATP> channel openers suppress the airway smooth muscle contraction, they have been investigated for the treatment of bronchial asthma. However, their potencies are different and the mechanisms involved are not fully clarified. Since there is a direct relationship between phosphatidylinositol (PI) response and airway smooth muscle contraction, we examined the effects of Y26763, a novel K_<ATP> channel opener, on PI and contractile responses of rat trachea.The studies were conducted under guidelines approved by the Animal Care Committee. Thirty-six Male Wistar rats weighing 250-350 g were anesthetized with 50 mg/kg intraperitoneal pentobarbital and the trachea was isolated. The trachea was chopped into 3-mm-wide ring segments for the contraction, or chopped into 1-mm-wide slices for PI response with a Mcllwain tissue chopper. First, the trachea rings were suspended between stainless hooks and the resting tension was adjusted to 1.5 g. Active contraction was induced with 0.55 muM Carbachol (CCh) and 30 min later, ring relaxation was induced by stepwise cumulative additions of cromakalim or Y26763. Second, the tracheal slices were incubated with [^3H]myo-inositol and various concentrations of cromakalim or Y26763, and 15 min later the slices were incubated with 0.55 muM CCh for 60 min. The [^3H]inositol monophosphate (IP_1) formed was separated from [^3H]myo-inositol by column chromatography and counted with a liquid scintillation counter. Statistical significance (P <0.05) was determined using ANOVA.CCh-induced tension was attenuated dose-dependently by either cromakalim or Y26763 with a significantly greater potency of Y26763. CCh-induced IP_1 accumulation was potentiated by cromakalim at a dose of 1 muM or greater, but not by Y26763.Results show that Y26763 has a stronger effect on airway smooth muscle relaxation than cromakalim, and suggest that the difference might be accounted in part by the differential effects on PI response.

由于 K_<ATP> 通道开放剂抑制气道平滑肌收缩，因此已研究它们用于治疗支气管哮喘。然而，它们的效力不同，所涉及的机制尚未完全阐明。由于磷脂酰肌醇 (PI) 反应与气道平滑肌收缩之间存在直接关系，我们研究了新型 K_<ATP> 通道开放剂 Y26763 对 PI 和大鼠气管收缩反应的影响。这些研究是根据动物保护委员会批准的指南进行的。雄性Wistar大鼠36只，体重250-350g，腹腔注射50mg/kg戊巴比妥麻醉，分离气管。将气管切成 3 毫米宽的环段以进行收缩，或用 Mcllwain 组织切碎器将气管切成 1 毫米宽的切片以进行 PI 反应。首先，将气管环悬挂在不锈钢钩之间，并将静息张力调节至1.5g。用0.55μM卡巴胆碱(CCh)诱导主动收缩，30分钟后，通过逐步累积添加cromakalim或Y26763诱导环松弛。其次，将气管切片与[^3H]肌醇和不同浓度的cromakalim或Y26763一起孵育，15分钟后将切片与0.55μM CCh一起孵育60分钟。通过柱色谱将形成的[ 3 H]肌醇单磷酸(IP_1)与[ 3 H]肌醇分离并用液体闪烁计数器计数。使用 ANOVA 确定统计显着性 (P <0.05)。 CCh 诱导的张力通过 Cromakalim 或 Y26763 剂量依赖性减弱，其中 Y26763 的效力显着增强。 Cch 诱导的 IP_1 积累被 1 muM 或更高剂量的 cromakalim 增强，但 Y26763 则没有增强作用。结果表明，Y26763 对气道平滑肌松弛的作用比 Cromakalim 更强，并表明这种差异可能部分归因于对 PI 反应的不同影响。

项目成果

Osamu Shibata: "Contractile and PI responses of rat trachea to anticholinesterase drugs." Can J Anaesth. 45 in press. (1998)

Osamu Shibata：“大鼠气管对抗胆碱酯酶药物的收缩和 PI 反应。”

Osamu Shibata: "Anticholinesterase drugs stimulate phosphati-dylinositol response in rat tracheal slices." Anesth Analg. 82. 1211-1214 (1996)

Osamu Shibata：“抗胆碱酯酶药物刺激大鼠气管切片中的磷脂酰肌醇反应。”

Toshiya Tsujita: "Effects of intravenous anesthetics on the contraction and response of rat trachea to PI." Res Commun Mol Path Pharmacol. 95. 287-303 (1997)

Toshiya Tsujita：“静脉麻醉药对大鼠气管收缩和对 PI 反应的影响。”

Toshya Tsujita: "Efbects of intravenous anesthelics on the contraction and response of rat trachea to phosphatidylinositol" Res Commun Mol path pharmacol. 95. 287-303 (1997)

Toshya Tsujita：“静脉麻醉药对大鼠气管收缩和对磷脂酰肌醇反应的影响”Res Commun Mol path drugl。

Shigeru Hashimoto: "Steroidal muscle relaxants attenuate the contractile and PI responses of rat trachea" Res Commun Mol Path Pharmacol. 100. 255-263 (1998)

Shigeru Hashimoto：“类固醇肌肉松弛剂减弱大鼠气管的收缩和 PI 反应”Res Commun Mol Path Pharmacol。