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&lt；ATP&gt；通道开放剂抑制气道平滑肌收缩，因此它们被用于治疗哮喘的研究。然而，它们的效力是不同的，涉及的机制也不完全清楚。由于磷脂酰肌醇(PI)的反应与气道平滑肌收缩有直接关系，我们研究了新型K&lt；ATP&gt；通道开放剂Y26763对大鼠气管PI和收缩反应的影响。研究是在动物保护委员会批准的指南下进行的。雄性Wistar大鼠36只，体重250~350g，以50 mg/kg戊巴比妥钠腹腔注射麻醉，分离气管。将气管切成3 mm宽的环状节段进行收缩，或切成1 mm宽的切片，用Mcllwain组织切割器进行PI反应。首先，将气管环悬吊在不锈钢钩之间，调整静息张力至1.5g，用0.55um卡巴胆碱(CCH)诱发主动收缩，30min后，逐步累积加入克罗卡林或Y26763，诱导气管环松弛。然后，将气管切片与肌醇和不同浓度的克罗卡林或Y26763孵育，15min后与0.55um CCH孵育60min。用柱层析法从肌醇中分离出一磷酸肌醇(IP_1)，并用液体闪烁计数器计数。用方差分析确定统计学意义(P&lt；0.05)。克罗卡林和Y26763均能剂量依赖性地减弱CCh引起的张力，其中Y26763的作用明显更强。Y26763可增强CCH诱导的IP_1聚集，但Y26763不能增强CCH诱导的IP_1聚集。结果表明，Y26763对气道平滑肌的松弛作用强于克罗卡林，提示这种差异可能与其对PI反应的差异性有关。

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。