iNOS-GC-cGMP信号活化参与了内毒素血症大鼠血管低反应性的发生机制  

iNOS-GC-cGMP signaling activation might be involved in vascular hyporeactivity in endotoxemic rats

作　　者：王海华[1,2] 闵志雪[1,2] 戚仁斌[3] 张根葆[2] 包鹏举[1,2] 胡钱国[1,2] 孙瑶[2] 

机构地区：[1]皖南医学院生理教研室,安徽芜湖241002 [2]皖南医学院蛇毒研究所,安徽芜湖241002 [3]暨南大学医学院病理生理教研室,广东广州510632

出　　处：《中国病理生理杂志》2012年第6期1076-1081,共6页Chinese Journal of Pathophysiology

基　　金：暨南大学国家中医药管理局病理生理实验室开放基金资助项目(No.2009ZD002);安徽省高等学校自然科学研究基金资助项目(No.KJ2007B022)

摘　　要：目的:探讨诱导型一氧化氮合酶(iNOS)-鸟苷酸环化酶(GC)-环磷酸鸟苷(cGMP)信号活化在内毒素血症大鼠血管低反应中的作用。方法:采用腹腔注射脂多糖(LPS)诱导大鼠内毒素血症模型,24只SD大鼠随机分为假手术组(sham组)、内毒素血症组(LPS组)、内毒素血症+多黏菌素B组(LPS+PMX-B组)和多黏菌素B组(PMX-B组)。颈总动脉插管记录大鼠平均动脉血压(MABP);检测各组大鼠血清中NO、iNOS和TNF-α的水平;用离体血管灌流方法,生物信号处理系统测定大鼠胸主动脉环的张力。结果:与sham组相比,LPS组大鼠MABP显著降低(P<0.01),LPS+PMX-B组大鼠明显高于LPS组(P<0.05),而PMX-B组与sham组比无统计学意义(P>0.05);生化检测发现LPS组大鼠血浆中NO、iNOS以及TNF-α水平显著高于sham组和LPS+PMX-B组(P<0.01)。同sham组相比,LPS组大鼠离体胸主动脉环对去氧肾上腺素(Phe)刺激的收缩反应及其对乙酰胆碱(ACh)的舒张反应均明显低下(P<0.01);与LPS组相比,LPS+PMX-B组的反应明显改善(P<0.01);氨基胍(AMG)预处理后,同sham组和PMX-B组相比,LPS组与LPS+PMX-B大鼠离体胸主动脉环对Phe(10-7～10-5mol.L-1)诱导下的各组血管环的收缩反应明显改善(P<0.05或P<0.01);亚甲蓝(MB)预处理后,同sham组和PMX-B组相比,LPS组与LPS+PMX-B组大鼠离体胸主动脉环对Phe(10-7～10-5mol.L-1)诱导下的各组血管环的收缩反应均得到改善(P<0.05或P<0.01);PMX-B组与sham组比差异无统计学意义(P>0.05)。结论:iNOS-GC-cGMP信号活化参与了内毒素血症大鼠血管低反应性;多黏菌素B改善内毒素血症大鼠血管低反应性,可能与中和内毒素、减少炎症因子释放、抑制iNOS-GC-cGMP信号活化有关。AIM： To evaluate the activation of inducible nitric oxide synthase （iNOS）-guanylate cyclase（GC）-cyclic guanosine monophosphate（cGMP） signaling on vascular hyporeactivity in endotoxemic rats. METHODS： Twenty-four SD rats were randomly divided into 4 groups as follows： sham operation group （sham group）, lipopolysaccharide group（LPS group）, LPS＋polymyxin B group （LPS＋PMX-B group） and polymyxin B group （PMX-B group）. Cannulation of the carotid artery was performed to record mean arterial blood pressure （MABP）. The levels of plasma NO, iNOS and TNF-α were detected. The tension of the thoracic aortic rings was measured by a biological analytical system. RESULTS： Compared with sham group, MABP in LPS group was significantly lower （P〈0.01）, whereas MABP in LPS＋PMX-B group was significantly higher than that in LPS group （P〈0.05）, and no statistical difference of MABP between PMX-B group and sham group was observed （P〉0.05）. The plasma levels of NO and iNOS in LPS group were significantly higher than those in sham group and LPS＋PMX-B group （P〈0.01）. The contraction of isolated thoracic aortic rings stimulated by phenylephrine and the relaxation response by acetylcholine in LPS group were significantly lower than those in sham group （P〈0.01）, whereas those in LPS＋PMX-B group were significantly improved （P〈0.01）. The vascular hyporeactivity to vasoconstrictors was completely reversed by pretreatment either with aminoguanidine, a selective iNOS inhibitor, or with methylene blue, an inhibitor of NO-sensitive GC. CONCLUSION： The iNOS-GC-cGMP signaling activation might be involved in vascular hyporeactivity in LPS-induced endotoxemic rats. Polymyxin B partly reverses the vascular hyporeactivity to vasoconstrictors by reducing the level of serum TNF-α, which may be mediated by the iNOS-GC-cGMP signal pathways to attenuate the overexpression of iNOS and NO production.

关 键 词：内毒素血症 脂多糖类 胸主动脉 一氧化氮合酶 多黏菌素B 

分 类 号：R363[医药卫生—病理学]