Effects of Propofol on Calcitonin Gene-related Peptide and Endothelium Derived Vasodilator Factors of Plasma and Cardiac Muscle in Spontaneously Hypertensive Rats<?xml:namespace prefix = o ns = "urn:schemas-microsoft-com:office:office" />

池　萍   硕士 
林财珠   教授 
杨锡馨   教授 
林　群   博士研究生 
林建清   硕士
北京佑安医院麻醉科, 北京 100054
福建医科大学附属第一医院麻醉科, 福州 350005
Ping chi, Caizhu Lin, Xixin Yang, Qun Li and Jianqing Li
Department of Anesthesiology, Beijing Youan Hospital,　Beijing, 100054
Department of Anesthesiology, First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005

ABSTRACT

Objective: To investigate the effects of Calcitonin gene-related peptide(CGRP), Nitric oxide(NO) and Prostacyclin(PGI₂) of plasma and cardiac muscle on Propofol's cardiovascular action in spontaneously hypertensive rats(SHR). Methods:  Male SHR and Wistar-kyoto rats (WKY) at age of 12~14 weeks were randomly allocated into 3 subgroups of each eight (n=8): (1) control groups (SC and WC); (2) low dose propofol groups (SL and WL); (3) high dose propofol groups (SH and WH). Anesthesia was induced with propofol 5mg•kg^-1, and maintained with intravenous propofol 30.60mg•kg^-1•h^-1 in the low and high groups respectively for 30 min. Systolic blood pressure, mean arterial pressure, diastolic blood pressure and heart rate were monitored. The contents of CGRP, NO and PGI₂ of plasma and cardiac muscle were determined. Results:  (1) The blood pressure and heart rate of both WKY and SHR decreased in time and dose dependent manner, but the changes were greater and earlier in SHR than in WKY. (2) The plasma levels of NO and PGI₂ in group SC were higher than WC; After infusion propofol, the levels of CGRP, NO and PGI₂ of plasma increased in both SHR and WKY(P<0.05 or P<0.01), which related to the dose of propofol; (3) In group SC the NO level of cardiac muscle was lower, but PGI₂ was higher than in WC (P<0.05); Propofol had no significant effects on those factors in WKY, but it increased NO and reduced the contents of PGI₂ in SHR. Conclusions:  (1) The enhancement of CGRP, NO and PGI₂ of plasma has the relationship with cardiovascular depression effects of propofol; (2) There is abnormity of NO and PGI₂ in cardiovascular system in SHR; (3) The cardiovascular depression effect is greater in SHR than in WKY,because not only those factors in blood but also in cardiac muscle are involved in SHR.
Key words:   Propofol;   Calcitonin gene-related peptide;  Nitric oxide; Prostacyclin;  Spontaneously hypertensive rats (SHR)

　　异丙酚具有一定的心血管抑制作用，降钙素基因相关肽(calcitonin gene-related peptide, CGRP)及血管内皮细胞分泌释放的舒张因子一氧化氮(nitric oxide, NO)和前列环素(prostacyclin, PGI2)具有广泛的心血管调节作用。本实验以研究人类原发性高血压的动物模型自发性高血压大鼠(spontaneously hypertensive rats, SHR)及同株系的正常Wistar-Kyoto(WKY)大鼠为对象，观察异丙酚对SHR血压心率及血浆和心肌中CGRP、NO及PGI2的影响，探讨CGRP、NO及PGI2在血流动力学变化中所起的作用。

材料与方法<?xml:namespace prefix = o ns = "urn:schemas-microsoft-com:office:office" />

　　动物及麻醉方法
　　12～14周SHR体重(286.5±24.7)g(北京医学科学院实验动物开发部提供)，与同龄雄性WKY大鼠体重(301.8±30.7)g(北京医学科学院实验动物开发部提供)，各24只均随机分为3个亚组：(1)对照组(SC和WC组，n=8)；(2)低剂量异丙酚组(SL和WL组，n=8)；(3)高剂量异丙酚组(SH和WH组，n=8)。2%戊巴比妥钠50mg/kg腹腔注射麻醉，股动脉和股静脉穿刺置管，动脉经压力换能器接多功能监护仪，静脉接微量注射泵，稳定20min后开始实验。SC和WC组静注生理盐水1.2ml•kg^-1后持续泵入盐水1.2ml•kg^-1•h^-1；SL和WL组异丙酚(英国捷利康公司) ５ml•kg^-1(容量1.2ml•kg^-1)诱导，30mg•kg^-1•h^-1 (盐水稀释为容量为1.2ml•kg^-1•h^-1)持续泵入维持麻醉；SH和WH组麻醉诱导同低剂量组，60mg•kg^-1•h^-1异丙酚维持。30min时停止输注，维持肛温37℃±0.5℃。
　　指标及检测
　　(1) 记录基础、给药后2、10、20和30min时的收缩压(SP)、平均动脉压(MAP)、舒张压(DP)和心率(HR)。
　　(2) 实验结束时股动脉取血，分别置于含不同抗凝剂的试管中混匀，分离血浆，-20°C保存待测血浆CGRP、NO及PGI2的含量。
　　(3) 取血完毕后立即开胸摘取心脏，4°C生理盐水冲洗，除去血液滤纸吸干水分置于液氮保存。制备匀浆时在左心室同一部位剪取心肌组织，称重后剪碎，移入微型玻璃匀浆器中在冰浴条件下按试剂盒的要求操作，离心提取上清，-20°C保存待测心肌中CGRP、NO及PGI2的含量。NO试剂盒由南京建成生物工程研究所提供，利用硝酸还原酶法测定NO,心肌组织蛋白的定量用双缩脲法。CGRP和PGI2用放免法测定，试剂盒由解放军总医院科技开发中心放免所提供，PGI2以其稳定代产物6-酮-前列腺素F1α(6-Keto-PGF1α)表示。
　　统计学分析　
　　数据以均数±标准差表示，采用SPSS10.0统计软件，用单因素方差分析、独立样本t-检验及直线相关分析，P<0.05为差异有显著性，以Microsoft Excel软件绘图。

结　果<?xml:namespace prefix = o ns = "urn:schemas-microsoft-com:office:office" />

      1 血压心率的变化　WKY及SHR组体重及心率无显著性差异，但SHR组SP、MAP和DP分别比WKY高43.39%、27.52%和18.67%(P均<0.05); WKY及SHR各自三个亚组间基础血压和心率的差异无显著性。输注异丙酚后，各组MAP和HR均呈时间剂量性下降，但SL及SH组MAP和HR出现下降的时间比WL及WH组早，SH组MAP降幅大于WH(30min时比基础分别下降31.89%和18.57%，P<0.05)而HR减慢的程度两者差异不显著(30min时分别减慢21.11%和18.98%，P>0.05), 见表１。
      2 血浆中因子的变化　SC组血浆NO、PGI2比WC组高(P<0.05或P<0.01)。输注异丙酚后，各组血浆CGRP、NO和PGI2随异丙酚的用量而增加(P<0.05或P<0.01)，见图1

3 心肌中因子的变化　SC组心肌NO低于WC而PGI2高于WC组(P <0.05)，CGRP变化不显著。输注异丙酚后，WL及WH组心肌中因子无显著性改变，而SL组NO增高，SH组除NO增高外PGI2下降(P<0.05或P<0.01)，见表2。

4 指标间的相关关系　WC组血浆PGI2与HR正相关(r=0.749,P<0.05);； WL组血浆NO与PGI2正相关(r=0.835,P<0.01), CGRP与NO、PGI2均正相关(r=0.809和0.765，P<0.05); SL组血浆CGRP与NO正相关(r=0.718,P<0.05), 心肌CGRP与PGI2负相关（r=-0.721,P<0.05）; WH,SC和SL组NO与HR均负相关(r分别为－0.731，－0.805和－0.735，P<0.05)，见图2和3。

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       池萍，女，副主任医师，2001年毕业于福建医科大学，获麻醉专业硕士学位，现在北京佑安医院麻醉科工作，主要从事肝胆外科和妇产科手术的麻醉。

　　林财珠，男，1954年生，主任医师，教授，硕士研究生导师，福建医科大学麻醉系主任，福建医科大学附属第一医院麻醉科主任，曾赴德国、美国参观和进修，主持省级科研课题４项，发表论文30余篇。