钙调蛋白在门静脉高压内脏高动力循环中的作用

摘要

Objective: To detect the variation of calmodulin ( CaM ) in the splanchnic arteries under portal hypertension ( PHT) , and investigate its effect on the hyperdynamic circulation of PHT and its possible mechanism . Method: Portal vein blood flow , portal vein pressure , the reaction of mesenteric microcirculation artery to norepinephrine (NE) were detected and compared between the control group (n=8) and PHT group (the rats with the liver cirrhosis caused by CCl4,n=8).The influence of the specific inhibitor of CaM-W-7 on the contractile response of isolated mesenteric microcirculation artery and the protein expression of CaM and phosphorylation of endothelial nitric oxide synthase ( p-eNOS) in mesentery artery were observed .Results:(1) Portal vein blood flow of PHT group was apparently lower than that of control group ,W-7 had no significant effect on portal vein blood flow of PHT group.(2) Portal vein pressure of PHT group was much higher than that of control group ,W-7 had little influence on reducing portal vein pressure of PHT group either .( 3 ) The contractile response of mesenteric microcirculation artery to NE in PHT group was decreased significantly , EC50 increases significantly , W-7 could improve this kind of hypoergia partially .(4) Compared with control group , the protein expression of CaM and p-eNOS in mesentery artery of PHT group increased quite a lot , W-7 could decrease the protein expression of p-eNOS significantly .Conclusion:The overproduced CaM in the mesenteric artery of the PHT rats may activate the eNOS by participating in or cooperating with the producing of p-eNOS, then enhance the synthesis of nitric oxide ( NO) , reduce the contractile response to norepinephrine of mesenteric microcirculation artery , cause the splanchnic vasodilatation , involve in the formation of splanchnic hyperdynamic circulation .%目的：检测钙调蛋白（calmodulin，CaM）在肝硬化门静脉高压（portal hypertension，PHT）的大鼠内脏动脉中的表达变化，探讨其在肝硬化PHT高动力循环中的作用及可能的机制。方法：检测并比较对照组（ n＝8）和四氯化碳（CCl4）诱导的肝硬化PHT组（n＝8）大鼠的门静脉血流量、门静脉压力、离体肠系膜微动脉对去甲肾上腺素（ norepinephrine ，NE）的反应性，CaM特异性抑制剂W-7对离体肠系膜微动脉收缩反应性、各组大鼠肠系膜动脉CaM和磷酸化内皮型一氧化氮合酶（ phosphorylation of endothelial nitric oxide synthase ， p-eNOS）的蛋白表达变化的影响。结果：（1） PHT组门静脉血流量明显低于对照组，W-7对PHT组门静脉血流量无明显改善作用；（2） PHT组门静脉压力明显高于对照组，W-7对PHT组门静脉压力亦无明显降低作用；（3） PHT组肠系膜微动脉对NE的收缩反应性明显降低，EC50明显增大，W-7能部分改善这种低反应性；（4） PHT组肠系膜动脉内CaM和p-eNOS的蛋白水平较对照组明显升高，W-7能明显降低PHT组肠系膜动脉内p-eNOS的蛋白表达。结论：CCl4诱导肝硬化PHT大鼠肠系膜动脉中过度生成的CaM可能通过参与或协同生成p-eNOS等方式来促进eNOS的活性增加，最终促进一氧化氮（nitric oxide，NO）的生物合成，降低肠系膜微动脉对NE的反应性，并引起内脏血管扩张，参与内脏高动力循环的形成。