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>频道开启器抑制了气道平滑肌收缩，因此已经对它们进行了调查以治疗支气管哮喘。但是，它们的效力是不同的，涉及的机制尚未完全澄清。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，因此我们检查了Y26763的影响，Y26763是一种新颖的K_ <ATP>启动器，对大鼠气管的PI和收缩反应的影响。根据该指南批准了该研究，该研究得到了动物保健委员会的批准。用50 mg/kg腹膜内五边形的五十六名雄性Wistar大鼠麻醉250-350 g的大鼠，并分离了气管。将气管切成3毫米宽的环段以进行收缩，或切成1毫米宽的切片，并用McLlwain Tissue Chopter将其切成1毫米宽的切片。首先，气管环在不锈钢钩之间悬浮，静止张力调整为1.5 g。用0.55 Mum Carbachol（CCH）诱导活性收缩，30分钟后，Cromakalim或Y26763的逐步累积添加诱导了环松弛。其次，将气管切片与[^3H]肌醇和各种浓度的Cromakalim或Y26763一起孵育，在15分钟后，将切片与0.55 MUM CCH孵育60分钟。形成的[^3H]肌醇单磷酸（IP_1）通过柱色谱法与[^3H]肌醇分离，并用液体闪烁计数器进行计数。使用ANOVA确定统计显着性（p <0.05）。CCH诱导的张力被Cromakalim或Y26763依赖于剂量，其效力明显更高的Y26763。 CCH诱导的IP_1积累以1 MM或更高的剂量增强，但不能通过Y26763进行，结果表明，Y26763比Cromakalim对气道平滑肌松弛的影响更强，并暗示可能由对PI响应的差异效应来解释差异。

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。

Osamu Shibata: "Anticholinesterase drugs stimulate phosphatidylinositol 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”Anesth Analg。