疲劳应激致血管内皮功能障碍与肾素-血管紧张素-醛固酮系统变化的关系及通络方药的干预

目的： 利用疲劳应激型血管内皮功能障碍动物模型，探讨过度疲劳状态下血管内皮功能障碍与肾素-血管紧张素-醛固酮系统（RAAS）及白细胞介素家族部分因子变化的关系及通络方药的干预作用。方法：健康雄性Wistar大鼠，随机分为对照组；高同型半胱氨酸（HCY）组；疲劳应激组；人参组；双参组；通心络组。放免方法检测血浆肾素活性（PRA）、血管紧张素Ⅱ（AngⅡ）、醛固酮（ALD)、白细胞介素1β（IL-1β）、白细胞介素-2（IL-2）、白细胞介素-6（IL-6）的水平及血管活性物质内皮素1（ET-1）、血栓素A2(TXA2)、前列环素I2（PGI2）、一氧化氮（NO）水平;ELISA方法检测去甲肾上腺素（NE）、白细胞介素-10（IL-10）水平。利用复杂系统分析方法分析血管内皮功能障碍与RAAS的关系。结果：与对照组比较，疲劳应激组缩血管因子ET-1、TXA2水平明显增高（P<0.01，P<0.05）,而舒血管因子PGI2、NO含量则显著降低（P＜0.01，P<0.01）；与对照组比较，疲劳应激组血浆肾素活性显著降低(P<0.01)，AngⅡ、IL-1β、IL-6显著升高（P<0.01，P<0.01），并高于HCY组（P<0.05, P<0.01, P<0.01）, NE含量也呈现升高趋势。与疲劳应激组比较，3种通络方药可显著降低血浆ET-1、AngⅡ、IL-1β、IL-6水平（P<0.01，P<0.01，P<0.05）及NE水平, 同时通心络组ALD显著升高（P<0.05）。复杂系统分析结果显示：在疲劳应激组，AngⅡ、IL-1β与ET之间，ALD与PGI2之间，ALD与NO之间分别构成3个相互独立的系统，它们之间均是按照复杂系统的最优化原则发生相互联系，并存在递变规律。而对照组、HCY组、通络方药干预组却不存在该联系。结论：长期处于过度疲劳状态，可诱发血管内皮功能障碍，并且与肾素-血管紧张素-醛固酮系统严重失平衡及植物神经功能失调有关，通络方药对此具有显著的改善作用。

Relationship between endothelial dysfunction and renin-angiotensin-aldosterone system under the condition of fatigue stress and effect of herbs to dredge collaterals

AIM: To investigate the mechanisms and relationship among endothelial dysfunction, renin-angiotensin-aldosterone system (RAAS) and family of interleukins under the condition of excessive fatigue, by using the rats with fatigue stress. METHODS: Healthy male Wistar rats were randomly divided into control group, homocysteine (HCY) group, fatigue stress group, renshen group, shuangshen group and tongxinluo group. Radioimmunoassay was carried out to detect plasma renin activity (PRA), angiotensin II (AngⅡ), aldosterone (ALD), endothelin (ET), thromboxane-2 (TXA2), prostaglandin I2 (PGI2) in plasma and interleukin-1β, 2, 6, 10 (IL -1β, IL -2, IL -6) in sera. ELISA was used to detect NE and IL -10. The content of nitric oxide (NO) in sera was also detected. The bioinformatical analysis was used to determine the relationship between RAAS and endothelial dysfunction. RESULTS: Compared with control group, the levels of ET-1 and TXA2 in fatigue stress group were significantly increased (P<0.01, P<0.05), but the content of PGI2 and NO was significantly decreased (P<0.01, P<0.01). Compared with control group, the renin activity in plasma of animals in fatigue stress group was significantly decreased (P<0.01), the AngⅡ, IL -1β, IL -6 level was significantly increased compared with the control group (P<0.01, P<0.01), and was significantly increased compared with the HCY group (P<0.05, P<0.01, P<0.01). The NE level showed the tendency of decrease in different degree. After the intervention of three kinds of herbs to dredge collaterals, the ET-1, AngⅡ, IL -1β, IL-6 level in plasma was decreased in different degree (P<0.05, P<0.01, P<0.01), and at the same time, the contents of NO and NE level were significantly increased (P<0.05). The ALD level in tongxinluo groups was apparently higher than that in control group and the fatigue stress group (P<0.05). The bioinformatics analysis showed that Ang II and ET, IL-1; PGI2 and ALD; NO and ALD composed of three subsystems and interrelated according to the principle of optimality of complex system, and gradual change regulation was also observed in fatigue stress group. However, in control group, HCY group and tongxinluo group, the same interrelation among subsystems was not existed. CONCLUSION: In a state of long-term excessive fatigue, vascular endothelial dysfunction may be induced, and is related with renin-angiotensin-aldosterone system imbalance and serious turbulence of the autonomic dysfunction. Herbs to dredge collaterals could improve it significantly. The results suggest that bearing excessive fatigue and pressure in long-term may be the potential risk factors to induce vascular endothelial dysfunction and further result in cardio-cerebro vascular diseases, Tongluo therapy may be one of the useful ways to prevent such diseases.