Nobe Koji, Suzuki Hikaru, Nobe Hiromi, Sakai Yasushi, Momose Kazutaka
Department of Pharmacology, School of Pharmaceutical Sciences, Showa University, Tokyo, Japan.
J Pharmacol Sci. 2003 Jul;92(3):267-82. doi: 10.1254/jphs.92.267.
The effect of the thromboxane A(2) analogue U46619 (9,11-dideoxy-11alpha,9alpha-epoxymethanoprostaglandin F(2)(alpha)) on sustained contraction in the mouse aorta was investigated. U46619 induced concentration-dependent (1 - 100 nM) increases in contraction. These contractile responses were enhanced significantly under high-glucose-physiological salt solution (HG-PSS) (2-fold greater than normal-PSS) conditions. This hyperactivation may be associated with aortic dysfunction in diabetes. However, the mechanisms remain unclear. HG-PSS enhanced U46619-induced accumulation of endogenous diacylglycerol (DG). Phospholipase C inhibitor (U73122) suppressed DG accumulation under normal conditions; however, suppression was not observed under high-glucose conditions. The HG-PSS-induced enhancement of contraction was inhibited by protein kinase C (PKC) inhibitor (calphostin C). This result indicated that accumulated DG might increase PKC activity, which then stimulates DG kinase activation as a feedback mechanism. DG kinase inhibition also suppressed HG-PSS-induced enhancement of contraction. Increased myo-inositol incorporation was detected under high-glucose conditions, indicating an acceleration of phosphatidylinositol (PI)-turnover. Moreover, rho kinase inhibitor (Y27632) suppressed U46619-induced contraction exclusively in normal-PSS. These findings indicated that HG-PSS treatment increases DG synthesis derived from incorporated glucose, PKC and DG kinase activation, and enhances the U46619-induced contraction via acceleration of PI-turnover. This series of responses may be involved in the dysfunction of aorta under high-glucose conditions occurring in association with diabetes.
研究了血栓素A(2)类似物U46619（9,11-二脱氧-11α,9α-环氧甲撑前列腺素F(2)(α)）对小鼠主动脉持续收缩的影响。U46619诱导收缩呈浓度依赖性（1 - 100 nM）增加。在高糖生理盐溶液（HG-PSS）条件下（比正常PSS大2倍），这些收缩反应显著增强。这种过度激活可能与糖尿病中的主动脉功能障碍有关。然而，其机制仍不清楚。HG-PSS增强了U46619诱导的内源性二酰甘油（DG）积累。磷脂酶C抑制剂（U73122）在正常条件下抑制DG积累；然而，在高糖条件下未观察到抑制作用。蛋白激酶C（PKC）抑制剂（钙泊三醇）抑制了HG-PSS诱导的收缩增强。该结果表明，积累的DG可能增加PKC活性，进而刺激DG激酶激活作为一种反馈机制。DG激酶抑制也抑制了HG-PSS诱导的收缩增强。在高糖条件下检测到肌醇掺入增加，表明磷脂酰肌醇（PI）周转加速。此外，rho激酶抑制剂（Y27632）仅在正常PSS中抑制U46619诱导的收缩。这些发现表明，HG-PSS处理增加了源自掺入葡萄糖的DG合成、PKC和DG激酶激活，并通过加速PI周转增强了U46619诱导的收缩。这一系列反应可能与糖尿病相关的高糖条件下主动脉功能障碍有关。
