内源性CO/NO在CCK-8逆转内毒素血症大鼠低血管反应性中的作用

目的:探讨HO-1-CO-cGMP和NOS-NO-cGMP细胞信号转导通路在八肽胆囊收缩素(CCK-8)逆转内毒素血症大鼠低血管反应性中的作用。方法:按照整体用药将大鼠分为4组:对照组、LPS组、CCK组及CCK+LPS组;用离体血管环张力测定技术,观察胸主动脉环(TARs)对苯肾上腺素(PE)累积收缩反应;分别用一氧化碳(CO)供体正铁血红素(He)、血红素氧合酶1(HO-1)抑制剂锌原卟啉(ZnPP-IX)、一氧化氮合酶(NOS)底物L-精氨酸(L-Arg)、诱生型一氧化氮合酶(iNOS)选择性抑制剂氨基胍(AG)、NOS抑制剂N^ω-硝基-L-精氨酸(L-NNA)、鸟苷酸环化酶(sGC)抑制剂亚甲兰(MB)预孵育后,测定TARs对PE的收缩反应。结果:单独应用CCK-8对血管张力无明显影响;预先注射CCK-8可明显逆转LPS所致的低血管反应性;LPS及CCK+LPS组TARs用ZnPP-IX或AG孵育,可部分逆转这种低血管反应性;经L-NNA或MB孵育,可使低血管反应恢复正常;用He或L-Arg孵育可不同程度加重低血管反应状态。结论:CCK-8本身不激活HO-1和iNOS,但可影响LPS诱导的HO-1和iNOS活性上升,减少CO/NO合成,从而使cGMP含量下降,对逆转内毒素血症大鼠低血管反应性有重要作用。

Effects of endogenous carbon monoxide/nitric oxide on cholecystokinin octapeptide reversed vascular hyporeactivity in endotoxemic rats

AIM:To explore the effects of cellular signal transduction pathways of heme oxygenase-1(HO-1)-carbon monoxide (CO)-cyclic GMP (cGMP) and nitric oxide synthase (NOS)-nitric oxide (NO)-cGMP on cholecystokinin octapeptide (CCK-8) reversed vascular hyporeactivity in endotoxemic rats. METHODS:According to the treatments given in vivo,rats were devided into four groups:control;lipopolysaccharide(LPS);CCK and CCK+LPS.Using isolated vascular ring tension detecting technique,thoracic aortic rings(TARs)were prepared and accumulation of contract ive responses to phenylephrine(PE)were measured under which the TARs were incubated with Hemin (He,donor of CO),Zinc-protoporphyrin-IX(ZnPP-IX,selective inhibitor of HO-1),L-arginine(L-Arg, substrate of NOS),aminoguanidine(AG,selective inhibitor of iNOS),N^ω-nitro-L-arginine(L-NNA,inhibitor of NOS)or methylene blue(MB,inhibitor of guanylyl cyclase),respectively. RESULTS:CCK-8 alone did not affect vascular tension. Injection of LPS induced the hyporeactivity of the TARs and was reversed by pretreatment of CCK-8. In LPS and CCK+LPS groups, the hyporeactivity was partly reversed by incubation of TARs with ZnPP-IX or AG, and restored to normal by incubation of TARs with L-NNA or MB. Incubation of TARs with He or L-Arg showed to make the vascular hyporeactivity worse in different degree.CONCLUSIONS:CCK-8 alone did not af ect the activity of HO-1 and iNOS but influenced the activity of these enzymes induced by LPS,which lead to reduced CO/NO production, decreased the content of cGMP and plays its important role in reversing vascular hyporeactivity in endotoxemic rats.