Nobe Koji, Sakai Yasushi, Nobe Hiromi, Takashima Junko, Paul Richard J, Momose Kazutaka
Department of Pharmacology, School of Pharmaceutical Sciences, Showa University, Tokyo, Japan.
J Pharmacol Exp Ther. 2003 Mar;304(3):1129-42. doi: 10.1124/jpet.102.040964.
The effect of the thromboxane A(2) analog 9,11-dideoxy-11alpha, 9alpha-epoxymethanoprostaglandin F(2alpha) (U46619) on spontaneous phasic contractions in the mouse portal vein was studied. U46619 induced concentration-dependent (1-100 nM) increases in amplitude, frequency, and contractile period (ON-time) of the contraction. Both amplitude and ON-time were enhanced significantly under high-glucose (HG; 4-fold greater than normal) conditions. This hyperactivation may be associated with portal vein dysfunction in diabetes. However, the mechanisms remain unclear. HG enhanced the U46619-induced accumulation of endogenous diacylglycerol (DG). Phospholipase C inhibition suppressed accumulation under normal conditions; however, this suppression was not observed under HG conditions. The HG-induced enhancement of U46619-induced contraction was inhibited by protein kinase C (PKC) inhibition. This finding indicated that accumulated DG might increase PKC activity. Activated PKC stimulated DG kinase activation as a feedback mechanism. DG kinase inhibition also suppressed the HG-induced enhancement of contraction. Increased myo-inositol incorporation was detected under HG conditions, indicating an acceleration of phosphatidylinositol (PI) turnover. This acceleration was inhibited by PKC and DG kinase inhibitors. These findings indicated that HG treatments increased DG synthesis derived from incorporated glucose, PKC, and DG kinase activation. These responses induce hyperactivation of the amplitude and contractile period of contraction mediated by acceleration of PI turnover. This series of responses may be involved in the dysfunction of the portal vein under the HG conditions occurring with diabetes.
研究了血栓素A(2)类似物9,11-二脱氧-11α,9α-环氧甲撑前列腺素F(2α)(U46619)对小鼠门静脉自发性相性收缩的影响。U46619诱导收缩幅度、频率和收缩期(开启时间)呈浓度依赖性(1-100 nM)增加。在高糖(HG;比正常高4倍)条件下，幅度和开启时间均显著增强。这种过度激活可能与糖尿病时门静脉功能障碍有关。然而，其机制尚不清楚。HG增强了U46619诱导的内源性二酰甘油(DG)积累。在正常条件下，磷脂酶C抑制可抑制积累；然而，在HG条件下未观察到这种抑制作用。蛋白激酶C(PKC)抑制可抑制HG诱导的U46619诱导的收缩增强。这一发现表明，积累的DG可能会增加PKC活性。激活的PKC作为一种反馈机制刺激DG激酶激活。DG激酶抑制也可抑制HG诱导的收缩增强。在HG条件下检测到肌醇掺入增加，表明磷脂酰肌醇(PI)周转率加快。这种加速被PKC和DG激酶抑制剂抑制。这些发现表明，HG处理增加了由掺入葡萄糖衍生的DG合成、PKC和DG激酶激活。这些反应通过PI周转率的加速诱导收缩幅度和收缩期的过度激活。这一系列反应可能参与了糖尿病时HG条件下门静脉的功能障碍。
