Yoshiyama Minoru, Nakamura Yasuhiro, Omura Takashi, Hayashi Tetsuya, Takagi Yasuhiro, Hasegawa Takao, Nishioka Hiroki, Takeuchi Kazuhide, Iwao Hiroshi, Yoshikawa Junichi
Department of Internal Medicine and Cardiology, Osaka City University Medical School, Osaka, Japan.
J Pharmacol Sci. 2004 Jun;95(2):196-202. doi: 10.1254/jphs.fpj03101x.
In this study, we investigated whether the Na(+)/Ca(2+) exchanger (NCX) inhibitor SEA0400 (2-[4-[(2,5-difluorophenyl)methoxy]phenoxy-5-ethoxyaniline) might have a protective effect against myocardial ischemia-reperfusion injury in rats. In particular, we focused on cardiac function using Doppler echocardiography and cardiac gene expression. We intravenously administered either SEA0400 and delivery vehicle or only the vehicle (as a control) to Wistar rats 5 min before ischemia was induced. Reperfusion was performed after 30 min of ischemia. At 1 week after ischemia-reperfusion injury, we assessed hemodynamics by inserting a polyethylene-tubing catheter, cardiac function by Doppler echocardiography, and myocardial mRNA expression was determined by Northern blot analysis. Left ventricular (LV) end-diastolic dimensions (LVDd) and LV end-diastolic volume (LVEDV) were significantly increased in the ischemia-reperfusion rat model group compared to the control group. The SEA0400-treated group had a significantly attenuated LVDd (P<0.05) and LVEDV (P<0.01) increase, compared to the vehicle-treated group. A decrease in the LV ejection fraction (P<0.05) was significantly prevented in the SEA0400-treated group compared to the vehicle-treated group. Moreover, mRNA expression of plasminogen activator inhibitor-1 in the non-infarcted LV of the SEA0400-treated group was significantly lower than in the vehicle-treated group (P<0.05). This study demonstrates that the NCX is an important mechanism for cell death in myocardial ischemia and reperfusion in rats. SEA0400 may prove to be a promising new drug in the clinical treatment of myocardial ischemia and reperfusion.
在本研究中，我们探究了钠/钙交换体（NCX）抑制剂SEA0400（2-[4-[(2,5-二氟苯基)甲氧基]苯氧基-5-乙氧基苯胺）对大鼠心肌缺血再灌注损伤是否具有保护作用。具体而言，我们通过多普勒超声心动图和心脏基因表达来关注心脏功能。在诱导缺血前5分钟，我们给Wistar大鼠静脉注射SEA0400和给药载体，或仅注射载体（作为对照）。缺血30分钟后进行再灌注。在缺血再灌注损伤后1周，我们通过插入聚乙烯管导管评估血流动力学，通过多普勒超声心动图评估心脏功能，并通过Northern印迹分析测定心肌mRNA表达。与对照组相比，缺血再灌注大鼠模型组的左心室（LV）舒张末期内径（LVDd）和LV舒张末期容积（LVEDV）显著增加。与载体处理组相比，SEA0400处理组的LVDd增加（P<0.05）和LVEDV增加（P<0.01）明显减轻。与载体处理组相比，SEA0400处理组显著预防了LV射血分数的降低（P<0.05）。此外，SEA0400处理组非梗死LV中纤溶酶原激活物抑制剂-1的mRNA表达显著低于载体处理组（P<0.05）。本研究表明，NCX是大鼠心肌缺血和再灌注中细胞死亡的重要机制。SEA0400可能被证明是心肌缺血和再灌注临床治疗中有前景的新药。
