Therapy for Advanced Atherosclerosis by Using Vascular Endocrinological System

我们尝试利用血管内分泌系统(瓜氨酸-精氨酸循环)治疗晚期动脉粥样硬化。我们还试图探讨诱导型一氧化氮合酶(INOS)和可溶性鸟苷环化酶在老年晚期动脉粥样硬化动物模型中的作用。首先，我们观察了兔动脉粥样硬化晚期T细胞和巨噬细胞中iNOS和ONOO^-的表达。应用L精氨酸而不是瓜氨酸可延缓动脉粥样硬化的进展。其次，用大鼠模型测定内皮和非内皮血管反应、eNOS和可溶性鸟苷环化酶(SGC)。用链脲佐菌素对青年(9周)、中年(54周)和老年(108周)雄性Wistar大鼠造成高血糖。诱导高血糖1~12周后，处死大鼠，观察胸主动脉无相关反应及分子分析。高血糖大鼠空腹血糖升高340±13 mg/dl。青年组(9周)无刺激反应和基础反应无明显变化。大鼠在高血糖状态下9周以上略有下降。与中青年大鼠(54周)相比，老年大鼠(108周)对硝酸甘油的内皮非依赖性反应减弱。此外，高血糖状态持续4周以上的患者其血糖水平也降低。NO刺激反应和基础反应在老年大鼠主动脉中略有降低，在高血糖时显著降低，并随高血糖持续时间的延长而显著降低。内皮型一氧化氮合酶和可溶性鸟苷环化酶蛋白在老年糖尿病大鼠呈下降趋势。此外，O_2^-随年龄增长和高血糖而升高。

We tried to use vascular endocrinological system (citrulline-arginine cycle) for therapy of advanced atherosclerosis. We also tried to investigate the role of inducible nitric oxide synthase (iNOS) and soluble guanylate cyclase in aged advanced atherosclerotic animal model. Firstly, we observed iNOS and ONOO^- in T cell and macrophages in rabbit advanced atherosclerosis. Application of L-arginine but not citrulline retards progression of atherosclerosis. Secondly, we determined dothelial and non-endothelial vascular responses, eNOS and soluble guanylate cyclase (sGC) using rats model. Hyperglycemia was induced by intraperitoneal injection of streptozotocin in young (9wks), middle aged (54wks) and elderly (108 wks) male wister rats. After 1 to 12 weeks of hyperglycemia induction, rats were sacrificed and NO related responses and molecular analyses were investigated in thoracic aortas. The fasting blood glucose was increased 340±13 mg/dl in hyperglycemic induced rats. NO stimulated and basal responses were not significantly changed in younger (9wks.) rats when they were slightly decreased under hyperglycemia for more than 9 weeks. Endothelium independent response by nitroglycerin was diminished in elderly rats (108 wks) as compared with those in younger and middle aged rats (54 wks). Further, it was diminished in status of hyperglycemia for longer than 4 weeks. NO stimulated and basal responses were slightly decreased in aortas of elderly rats, and significantly decreased in hyperglycemia and depending on the duration of hyperglycemia. eNOS and soluble guanylate cyclase protein tended to decrease in aged diabetic rats. Further, O_2^- was increased by aging and hyperglycemia.