通阳逐瘀法激活MAPKs/IL-6信号通路抗急性心肌缺血作用及机制研究
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摘要
目的
通过辛温通阳中药葱白提取物和逐瘀中药大黄提取物不同配伍比例治疗急性心肌缺血的对比研究,探讨通阳逐瘀法对急性心肌缺血大鼠MAPKs/IL-6信号通路的调节作用及机制研究,初步揭示通阳逐瘀法治疗急性心肌缺血的生物学基础。
方法
本研究选用健康纯种SD雄性大白鼠,体重为200-230克,3-4月龄64只随机分为正常对照组、空白模型组、葱白提取物组、葱白提取物与大黄提取物7：3、5：5、3：7组、大黄提取物组及硝酸甘油组,共8组,每组8只。参照郭延松等的方法制备急性心肌缺血模型,适应性喂养1周后,将大鼠腹腔注射3.5%戊巴比妥钠腹腔注射(35mg/kg)麻醉,仰位固定于鼠板上,将大鼠与powerlab/8s型八导数据分析记录仪连接好,于开胸前记录一段正常心电图,随后将大鼠气管切开连Y型气管插管,另一端连与动物微量呼吸机出气孔,以10x60ml/min持续进气,然后开胸结扎左冠状动脉制备急性心肌缺血模型,于造模后十二指肠给药,4小时后观察相关指标,各药物组给相应浓度药物,假手术组与模型组给予同体积的生理盐水,用注射器于结扎后5分钟给药,4h后采集血样及心脏。在腹部中线偏左开口找到十二指肠备用,用生理盐水纱布覆盖伤口,4小时后采集血样及心肌组织,观察相关指标,给药体积为2ml/kg,正常对照组和空白模型组给与同等体积生理盐水、葱白提取物组按600mg·kg-1给药、大黄提取物组按400mg·kg-1给药、葱白提取物与大黄7：3、5：5、3：7组按葱白与大黄上述浓度混合、硝酸甘油组按80mg·kg-1给药,观察4小时后,再次检测心电图,观测完毕后,立即以血管钳暂时夹闭大鼠胸壁,快速行大鼠腹主动脉取血,立即将其中2ml血注入含有10%EDTA二钠30μl和胰肽酶40μl的试脉中,混匀,4℃,3000rpm离心10min,分离血浆,放置于-70℃冰箱中保存待测,其余血3500rpm离心20min,取上清,分装后置于-70℃冰箱中保存待测。测定前,将样本置于冷水中复融,混匀,再次4℃,3000rpm离心5min,取上清液测定。通过标准Ⅱ导心电图观测(标准电压为0.1mv,走纸速度50mm/s),分别分别记录给药前后心电图,测量ST段上移平均数,给药前后心电图ST段变化。
通过HE染色分析大鼠心肌组织病理变化,ELISA法检测血清cTnI、 CK-MB、LDH、IL-6的含量。采用化学方法检测心肌组织H2S含量。WesternBlot法检测P-ERK、P-JNK、P-p38在急性心肌缺血大鼠心肌组织中的表达,用实时荧光定量PCR技术检测急性心肌缺血大鼠心肌组织中IL-6mRNA的表达；采用超声技术检测急性心肌缺血大鼠心功能。
结果
1.对急性心肌缺血大鼠心电图、左心功能、心肌损伤标志物的影响：与正常对照组之间比较,空白模型组大鼠ST段显著升高(P<0.01)；与空白模型组比较,大黄提取物组无显著性差异(P>0.05),其余各治疗组织组均可降低大鼠ST段(P<0.05,P<0.01),葱白提取物组效果最为显著(P<0.01),通阳逐瘀组之间没有显著差异(P>0.05)。
与正常对照组比较,空白模型组大鼠血清cTnI明显升高(P<0.01)；与空白模型组比较,各治疗组大鼠血清cTnI水平明显降低(P<0.05,P<0.01),葱白提取物组降低最为明显,优于各治疗组,通阳逐瘀组之间没有显著差异(P>0.05)
与正常对照组比较,空白模型组大鼠血清CK-MB明显升高(P<0.01)。与空白模型组比较,各治疗组大鼠血清CK-MB明显降低(P<0.05,P<0.01),葱白提取物组与硝酸甘油组降低最为明显,组间无显著差异(P>0.05),葱白提取物组疗效优于大黄提取物组及通阳逐瘀组。
与正常对照组比较,空白模型组大鼠血清LDH明显升高(P<0.01)。与空白模型组比较,各治疗组大鼠血清LDH明显降低(P<0.05,P<0.01),大黄提取物组、通阳逐瘀组和硝酸甘油组之间相比较无显著性差异,优于葱白提取物组,通阳逐瘀组之间没有显著差异(P>0.05)。
与正常组比较,空白模型组EF、FS、Em/Am值明显降低(P<0.01)；与模型组比较,各治疗组EF, FS值、Em/Am(除大黄提取物组外)值明显升高(P<0.01)；对EF值和FS值的影响,通阳逐瘀组之间、通阳逐瘀组和葱白提取物组没有显著差异(P>0.05),优于大黄提取物组和硝酸甘油组(P<0.05)；对Em/Am值的影响,通阳逐瘀组之间、通阳逐瘀组和硝酸甘油组没有显著差异(P>0.05),优于葱白提取物组。
2.对急性心肌缺血大鼠组织形态学的影响心肌组织切片经HE染色,光镜下观察各组大鼠心肌细胞病理变化,结果显示：正常组：大部分心肌纤维结构正常,排列成束,心肌细胞椭圆形或短梭形,位于细胞中央,肌纤维间散在毛细血管。模型组：心肌纤维肿胀,部分心肌纤维断裂,可见小灶性肌纤维坏死,肌纤维结构不清清；肌纤维间毛细血管扩张充血,及炎细胞灶性浸润。葱白提取物组大部分心肌纤维结构正常,仅见少数肌纤维肿胀,排列成束,肌纤维间散在毛细血管,未见灶性坏死。通阳逐瘀(7：3)组部分心肌纤维结构正常,见少数肌纤维肿胀,肌纤维间毛细血管增多。其余各治疗组可见部分心肌肿胀,结构模糊,部分心肌纤维断裂,肌纤维间少数毛细血管扩张充血管增多。
3.对急性心肌缺血大鼠心肌组织H2S的影响与正常对照组比较,空白模型组H2S水平明显降低(P<0.01)；与空白模型组比较,各治疗组H2S水平显著升高(P<0.01),通阳逐瘀(7：3)组升高H2S水平最为显著,明显优于葱白提取物组、大黄提取物组、硝酸甘油组和其它通阳逐瘀组。
4.对急性心肌缺血大鼠MAPKs的影响与正常对照组比较,模型组P-ERK的表达显著升高(22.54%),提示造模成功。与模型组比较,除通阳逐瘀(7：3)组外(P>0.05),其余各治疗组P-ERK显著减少,各干预组抑制率分别为：通阳逐瘀(5：5)组为6.29%、硝酸甘油组为8.94%、葱白提取物组为9.05%、大黄提取物组为11.17%、通阳逐瘀(3：7)组为13.34%。
与正常对照组比较,模型组P-JNK蛋白表达显著升高(44.58%),提示造模成功。与模型组比较,各治疗组P-JNK显著降低。各干预组抑制率分别为：通阳逐瘀(3：7)组为14.17%、通阳逐瘀(5：5)组为24.83%、大黄提取物组为25.59%、葱白提取物组为26.37%、硝酸甘油组为26.56%、通阳逐瘀(7：3)组为31.73%。
与正常对照组比较,模型组P-p38蛋白表达显著升高(88.0%),提示造模成功。与模型组比较,各治疗组P-p38表达显著降低,各干预组抑制率分别为：大黄提取物组为18.91%、通阳逐瘀(3：7)组为24.31%、通阳逐瘀(5：5)组为31.64%、葱白提取物组为44.20%、通阳逐瘀(7：3)组为45.25%、硝酸甘油组为45.29%。
5.对急性心肌缺血大鼠心肌组织IL-6的影响与正常对照组比较,模型组大鼠血清IL-6含量明显升高(P<0.01)；与空白模型组比较,除通阳逐瘀(3：7)组外,其余各治疗组均可以降低血清IL-6含量,通阳逐瘀(7：3)组降低血清IL-6水平最为显著(P<0.01),优于通阳逐瘀(5：5)组、葱白提取物组、大黄提取物组和硝酸甘油组(P<0.05)。
与正常对照组比较,模型组大鼠心肌组织IL-6mRNA水平明显升高(P<0.05),扩增倍数为1.00；与空白模型组比较,各治疗组均可降低IL-6mRNA水平,个干预组抑制率分别为：葱白提取物组为16.49%、硝酸甘油组为27.33%、大黄提取物组为30.5%、通阳逐瘀(5：5)组为41.32%、通阳逐瘀(3：7)组为41.96%、其中通阳逐瘀(7：3)组为45.98%。
结论
①通阳逐瘀法干预急性心肌缺血的免疫机制可能与激活MAPKs及IL-6mRNA表达,影响MAPKs/IL-6信号转导通路有关。
②通阳逐瘀法通过改善心电图、提高心功能、抑制心肌酶外漏,减轻心肌损伤。
③通阳逐瘀法通过对气体信号分子H2S的调控发挥对缺血心肌的保护作用。
④通阳逐瘀不同比例组中以葱白：大黄(7：3)组疗效为优,但是由于作用环节和作用靶点的不同,药物成分的目前有些不清楚,对其整体优势的评价还有待进一步深入研究。
Research Purpose
By the comparative study of the different compatibility proportion of Chinese traditional medicine extracted from f istular onion stalk and rhubarb on the treatment of acute myocardial ischemia, the study aims to discuss the regulation effect and mechanism of blood stasis removing method on acute myocardial ischemia in rat MAPKs/IL-6signal pathway, thus preliminarily reveal the biological basis of the treatment of acute myocardial ischemia with the blood stasis removing method.
Method
This research selected64healthy pure SD male rats weighed for200-230g and aged3-4months, then they were randomly divided into normal control group, blank model group, fistular onion stalk extraction group, fistular onion stalk extraction and rhubarb extraction group of7:3,5:5,3:7, rhubarb extraction group and the nitroglycerin group, with a total8groups and8rats in each group. The acute myocardial ischemia models were prepared according to the acute myocardial ischemia model from Guo Yansong, rats were adaptively fed for1week, and were injected with3.5%sodium pentobarbital intraperitoneal (35mg/kg) for anesthesia, Rats were fixed supinely and were connected with the power lab/8s eight guided data analysis recorder, opened the chest to get records of a normal ECG, then the rats'pulses were cut to connect with the Y pulse interpolation, with the other end connected with the animal trace ventilator outlet, with a continuous inlet of10x60ml/min, and legated the left coronary artery to prepare the myocardial ischemia model, then delivered the drugs, then observed the indexes3hours later, each group was treated with the corresponding concentration of one drug, sham operation group and model group were given the same volume of saline, with a syringe5minutes after occlusion, blood collection and heart were taken4h later. Cut at the left of abdominal midline to locate the duodenum, covered the wound with saline gauze, took the blood and myocardial tissues4hours later, observed the relevant index, the drug-delivery volume was of2ml/kg, the normal control group and blank model group were given an equal volume of saline, the fistular onion stalk extraction group was delivered the drug at600mg kg-1, rhubarb extraction group at400mg kg-1, fistular onion stalk and rhubarb were mixed with the corresponding concentration of7:3,5:5,3:7in different groups, nitroglycerin group was delivered at80mg kg-1, observed for3h, and conducted ECG detection again, after observation, immediately clamped the rat thoracic wall temporarily by cl ipping the fast lines of rats, immediately took blood from the abdominal aorta and injected2ml blood into to the tube containing30UL of10%EDTA sodium and40ul of pancreatic peptide enzyme, mixed at4℃, centrifugal at3000rpm for10min, separated the plasma, and placed it in the refrigerator at-70℃for testing, the remaining blood of was centrifuged at3500rpm for20min, took the supernatant, packed and placed in the refrigerator at-70℃. Before the test, the sample was melted in cold water, mixed, and centrifuged at3500rpm for5min at4℃, then took the supernatant for testing. Recorded the electrocardiogram before and after administration, measured the average of ST segment shift and the changes of electrocardiogram of ST segment, with the standard Ⅱ electroca-rdiogram observation (standard voltage was0.1mv, paper shift speed was50mm/s). The pathological changes of rat myocardial tissues were analyzed through HE staining, the serum content of cTnl, CK-MB, LDH, IL-6were detected with ELISA assay. Chemical method was taken to detect myocardial H2S content. Western Blot method was applied for the detection of P-ERK, P-JNK, P-p38in acute myocardial ischemia in rat tissues, the real time fluorescent quantitative PCR technique was taken for the detection of IL-6mRNA expression in acute myocardial ischemia in myocardial tissues of rats; ultrasonic technology was used in the detection of cardiac function in acute myocardial ischemia rats;
Results
1. The influence on the ECG, left ventricular function and markers for myocardial infarction of acute myocardial ischemia rats:in comparison with the normal control group, the ST segment increased significantly in the blank model group (P<0.01); and the blank model group got no significant difference from the rhubarb extraction group (P>0.05), all the other treatment tissue groups could reduce rat ST segments (P<0.05, P<0.01), the effect in fistular onion stalk extraction group was the most remarkable (P<0.01), the groups of blood stasis removing method got no signi ficant difference (P>0.05).
Compared with the normal group, the serum cTnl of rats in blank model group was significantly increased (P<0.01); and serum cTnI of rats in all the treatment group were significantly decreased when compared with the blank model group (P<0.05, P<0.01), the decrease in fistular onion stalk extraction group was most obvious, and was better than any treatment group, the groups of blood stasis removing method got no significant difference (P>0.05).
Compared with the normal group, the serum CK-MB of rats in blank model group was significantly increased (P<0.01); and serum CK-MB of rats in all the treatment group were significantly decreased when compared with the blank model group (P<0.05, P<0.01), the decrease in fistular onion stalk extraction group and the nitroglycerin group was most obvious, and with no significant difference between the groups (P>0.05), the effect in fistular onion stalk extraction group was better than that in the rhubarb extraction group and the group of blood stasis removing method.
Compared with the normal group, the serum LDH of rats in blank model group was significantly increased (P<0.01); and serum LDH of rats in all the treatment group were significantly decreased when compared with the blank model group (P<0.05,P<0.01), there were no significant difference among the rhubarb extraction group, group of blood stasis removing method and the nitroglycerin group, and the effect was better than that in the fistular onion stalk extraction group, no significant differences were found in the groups of blood stasis removing method (P>0.05).
Compared with the normal group, EF, FS, Em/Am values in the model group were significantly decreased (P<0.01); compared with the model group, the EF, FS, Em/Am values in each treatment group (except the rhubarb extraction group) were significantly increased (P<0.01); as for the influence on the EF value and FS value, no significant difference was found between the group of blood stasis removing method and the group of fistular onion stalk extraction group (P>0.05), but the results were still better than that in the rhubarb extraction group and the nitroglycerin group (P<0.05); as for the influence on the Em/Am value, there were no significant differences among the groups of blood stasis removing method, or between the group of blood stasis removing method and the nitroglycerin group (P>0.05), and the effect was better than that in the fistular onion stalk extraction group.
2. Morphological influences on the rat tissues of acute myocardial ischemia The syocardial tissue sections were HE stained, and the rat myocardial cells were observed with light microscopy to find out pathological changes, the results showed that, for the normal group:most of the myocardial fibers were of normal structure, and were arranged in bundles, cardiac muscle cells were in the oval-shaped or in the shape of short spindle, they were located in the cell center and the muscle fibers scattered in the capillaries. For the model group:myocardial fiber was swelling, part of the myocardial fiber fracture was found, small focal muscle fiber necrosis was noticed, and the muscle fiber structure was unclear; muscle fiber capillary was dilatated and congested, and focal infiltration of inflammatory cells was found. Most of the myocardial fiber structure of the fistular onion stalk extraction group was normal, and only a small number of muscle fiber swelling was found, which were arranged in bundles, the muscle fibers were scattered in the capillaries, and no focal necrosis was found. The groups of blood stasis removing method (7:3), in this group, part of the myocardial fiber structure was normal, a small number of muscle fiber swelling was detected, capillaries between the muscle fibers increased. In the rest of the treatment groups, focal myocardial swelling was found, with blurred structure, and part of the myocardial fiber was broken, and telangiectasia was found in a few capillaries of muscle fibers.
3. Influence on the myocardial tissue of H2S of rats with acute myocardial ischemia Compared with the normal control group, the H2S decreased significantly in the blank model group (P<0.01); and the H2S level of each treatment group was significantly increase-ed when compared wi th the blank model group (P<0.01), the increase was most obvious in the group of blood stasis removing method (7:3), and the results were significantly better than that in the fistular onion stalk extraction group, rhubarb extraction group, the nitroglycerin group and other groups of blood stasis removing method.
4. The influence on MAPKs of rats with acute myocardial ischemia
Compared with the normal control group, the P-ERK expression in model group was significantly increased (22.54%), suggesting a successful modeling. Compared with the model group, except for the group of blood stasis removing method (7:3)(P>0.05), P-ERK was significantly decreased in the other treatment groups, the inhibitory rate of each intervention group were:6.29%in the group of blood stasis removing method (5:5),8.94%in the nitroglycerin group,9.05%in the fistular onion stalk extraction group,11.17%in the rhubarb extraction group, and it was13.34%in the group of blood stasis removing method (3:7).
Compared with the normal control group, the P-JNK protein expression in model group was significantly increased (44.58%), suggesting a successful modeling. Compared with the model group, the P-ERK was significantly decreased in each treatment group, and the inhibitory rate of each intervention group were:14.17%in the group of blood stasis removing method (3:7),24.83%in the group of blood stasis removing method (5:5),25.59%in the rhubarb extraction group,26.37%in the fistular onion stalk extraction group,26.56%in the nitroglycerin group, and31.73%in the group of blood stasis removing method (7:3).
Compared with the normal control group, the P-p38protein expression in model group was significantly increased (88.0%), suggesting a successful modeling. Compared with the model group, the P-P38expression was significantly decreased in each treatment group, and the inhibitory rate of each intervention group were:18.91%in the rhubarb extraction group,24.31%in the group of blood stasis removing method (3:7),31.64%in the group of blood stasis removing method (5:5),44.20%in the fistular onion stalk extraction group,45.25%in the group of blood stasis removing method (7:3) and45.29%in the nitroglycerin group.
5. The influence on myocardial tissue IL-6of rats with acute myocardial ischema Compared with the normal control group, the IL-6level of rats in model group was significantly increased (P<0.01), compared with the model group, except for the group of blood stasis removing method (3:7)(P>0.05), all the other treatment groups could decrease the level of serum IL-6, and the decrease of serum IL-6was most significant in the group of blood stasis removing method (7:3)(P<0.01), which was better than that in the group of blood stasis removing method(5:5), the rhubarb extraction group, the fistular onion stalk extraction group and the nitroglycerin group (P<0.05).
Compared with the normal control group, the IL-6mRNA level of heart muscle tissue of rats in model group was significantly increased (P<0.05), with the amplification of1.00; compared with the blank model group, all the treatment groups can reduce the level of IL-6mRNA, and the inhibition rate of each intervention group was:16.49%in the fistular onion stalk extraction group,27.33%in the nitroglycerin group,30.5%in the rhubarb extraction group,41.32%in the group of blood stasis removing method (5:5),41.96%in the group of blood stasis removing method (3:7), and45.98%in the group of blood stasis removing method (7:3)
Conclusion
1. The immune mechanisms of the blood stasis removing method intervening acute myocardial ischemia may be related with the activation of MAPKs and IL-6mRNA expression and the influence on MAPKs/IL-6signal transduction pathway.
2. The blood stasis removing method could inhibit myocardial enzyme leakage and reduce myocardial injury by improving ECG, and enhancing the cardiac function.
3. The blood stasis removing method protects the ischemic myocardium through the regulation of gaseous molecules of H2S.
4. Of the different proportions of blood stasis removing, the group of scallion stalk with rhubarb (7:3) got the best efficacy, but due to the differences of the action segments and targets, and the unclear drug ingredients, further studies on the evaluation of its overall advantage are still in need.
通过辛温通阳中药葱白提取物和逐瘀中药大黄提取物不同配伍比例治疗急性心肌缺血的对比研究,探讨通阳逐瘀法对急性心肌缺血大鼠MAPKs/IL-6信号通路的调节作用及机制研究,初步揭示通阳逐瘀法治疗急性心肌缺血的生物学基础。
方法
本研究选用健康纯种SD雄性大白鼠,体重为200-230克,3-4月龄64只随机分为正常对照组、空白模型组、葱白提取物组、葱白提取物与大黄提取物7：3、5：5、3：7组、大黄提取物组及硝酸甘油组,共8组,每组8只。参照郭延松等的方法制备急性心肌缺血模型,适应性喂养1周后,将大鼠腹腔注射3.5%戊巴比妥钠腹腔注射(35mg/kg)麻醉,仰位固定于鼠板上,将大鼠与powerlab/8s型八导数据分析记录仪连接好,于开胸前记录一段正常心电图,随后将大鼠气管切开连Y型气管插管,另一端连与动物微量呼吸机出气孔,以10x60ml/min持续进气,然后开胸结扎左冠状动脉制备急性心肌缺血模型,于造模后十二指肠给药,4小时后观察相关指标,各药物组给相应浓度药物,假手术组与模型组给予同体积的生理盐水,用注射器于结扎后5分钟给药,4h后采集血样及心脏。在腹部中线偏左开口找到十二指肠备用,用生理盐水纱布覆盖伤口,4小时后采集血样及心肌组织,观察相关指标,给药体积为2ml/kg,正常对照组和空白模型组给与同等体积生理盐水、葱白提取物组按600mg·kg-1给药、大黄提取物组按400mg·kg-1给药、葱白提取物与大黄7：3、5：5、3：7组按葱白与大黄上述浓度混合、硝酸甘油组按80mg·kg-1给药,观察4小时后,再次检测心电图,观测完毕后,立即以血管钳暂时夹闭大鼠胸壁,快速行大鼠腹主动脉取血,立即将其中2ml血注入含有10%EDTA二钠30μl和胰肽酶40μl的试脉中,混匀,4℃,3000rpm离心10min,分离血浆,放置于-70℃冰箱中保存待测,其余血3500rpm离心20min,取上清,分装后置于-70℃冰箱中保存待测。测定前,将样本置于冷水中复融,混匀,再次4℃,3000rpm离心5min,取上清液测定。通过标准Ⅱ导心电图观测(标准电压为0.1mv,走纸速度50mm/s),分别分别记录给药前后心电图,测量ST段上移平均数,给药前后心电图ST段变化。
通过HE染色分析大鼠心肌组织病理变化,ELISA法检测血清cTnI、 CK-MB、LDH、IL-6的含量。采用化学方法检测心肌组织H2S含量。WesternBlot法检测P-ERK、P-JNK、P-p38在急性心肌缺血大鼠心肌组织中的表达,用实时荧光定量PCR技术检测急性心肌缺血大鼠心肌组织中IL-6mRNA的表达；采用超声技术检测急性心肌缺血大鼠心功能。
结果
1.对急性心肌缺血大鼠心电图、左心功能、心肌损伤标志物的影响：与正常对照组之间比较,空白模型组大鼠ST段显著升高(P<0.01)；与空白模型组比较,大黄提取物组无显著性差异(P>0.05),其余各治疗组织组均可降低大鼠ST段(P<0.05,P<0.01),葱白提取物组效果最为显著(P<0.01),通阳逐瘀组之间没有显著差异(P>0.05)。
与正常对照组比较,空白模型组大鼠血清cTnI明显升高(P<0.01)；与空白模型组比较,各治疗组大鼠血清cTnI水平明显降低(P<0.05,P<0.01),葱白提取物组降低最为明显,优于各治疗组,通阳逐瘀组之间没有显著差异(P>0.05)
与正常对照组比较,空白模型组大鼠血清CK-MB明显升高(P<0.01)。与空白模型组比较,各治疗组大鼠血清CK-MB明显降低(P<0.05,P<0.01),葱白提取物组与硝酸甘油组降低最为明显,组间无显著差异(P>0.05),葱白提取物组疗效优于大黄提取物组及通阳逐瘀组。
与正常对照组比较,空白模型组大鼠血清LDH明显升高(P<0.01)。与空白模型组比较,各治疗组大鼠血清LDH明显降低(P<0.05,P<0.01),大黄提取物组、通阳逐瘀组和硝酸甘油组之间相比较无显著性差异,优于葱白提取物组,通阳逐瘀组之间没有显著差异(P>0.05)。
与正常组比较,空白模型组EF、FS、Em/Am值明显降低(P<0.01)；与模型组比较,各治疗组EF, FS值、Em/Am(除大黄提取物组外)值明显升高(P<0.01)；对EF值和FS值的影响,通阳逐瘀组之间、通阳逐瘀组和葱白提取物组没有显著差异(P>0.05),优于大黄提取物组和硝酸甘油组(P<0.05)；对Em/Am值的影响,通阳逐瘀组之间、通阳逐瘀组和硝酸甘油组没有显著差异(P>0.05),优于葱白提取物组。
2.对急性心肌缺血大鼠组织形态学的影响心肌组织切片经HE染色,光镜下观察各组大鼠心肌细胞病理变化,结果显示：正常组：大部分心肌纤维结构正常,排列成束,心肌细胞椭圆形或短梭形,位于细胞中央,肌纤维间散在毛细血管。模型组：心肌纤维肿胀,部分心肌纤维断裂,可见小灶性肌纤维坏死,肌纤维结构不清清；肌纤维间毛细血管扩张充血,及炎细胞灶性浸润。葱白提取物组大部分心肌纤维结构正常,仅见少数肌纤维肿胀,排列成束,肌纤维间散在毛细血管,未见灶性坏死。通阳逐瘀(7：3)组部分心肌纤维结构正常,见少数肌纤维肿胀,肌纤维间毛细血管增多。其余各治疗组可见部分心肌肿胀,结构模糊,部分心肌纤维断裂,肌纤维间少数毛细血管扩张充血管增多。
3.对急性心肌缺血大鼠心肌组织H2S的影响与正常对照组比较,空白模型组H2S水平明显降低(P<0.01)；与空白模型组比较,各治疗组H2S水平显著升高(P<0.01),通阳逐瘀(7：3)组升高H2S水平最为显著,明显优于葱白提取物组、大黄提取物组、硝酸甘油组和其它通阳逐瘀组。
4.对急性心肌缺血大鼠MAPKs的影响与正常对照组比较,模型组P-ERK的表达显著升高(22.54%),提示造模成功。与模型组比较,除通阳逐瘀(7：3)组外(P>0.05),其余各治疗组P-ERK显著减少,各干预组抑制率分别为：通阳逐瘀(5：5)组为6.29%、硝酸甘油组为8.94%、葱白提取物组为9.05%、大黄提取物组为11.17%、通阳逐瘀(3：7)组为13.34%。
与正常对照组比较,模型组P-JNK蛋白表达显著升高(44.58%),提示造模成功。与模型组比较,各治疗组P-JNK显著降低。各干预组抑制率分别为：通阳逐瘀(3：7)组为14.17%、通阳逐瘀(5：5)组为24.83%、大黄提取物组为25.59%、葱白提取物组为26.37%、硝酸甘油组为26.56%、通阳逐瘀(7：3)组为31.73%。
与正常对照组比较,模型组P-p38蛋白表达显著升高(88.0%),提示造模成功。与模型组比较,各治疗组P-p38表达显著降低,各干预组抑制率分别为：大黄提取物组为18.91%、通阳逐瘀(3：7)组为24.31%、通阳逐瘀(5：5)组为31.64%、葱白提取物组为44.20%、通阳逐瘀(7：3)组为45.25%、硝酸甘油组为45.29%。
5.对急性心肌缺血大鼠心肌组织IL-6的影响与正常对照组比较,模型组大鼠血清IL-6含量明显升高(P<0.01)；与空白模型组比较,除通阳逐瘀(3：7)组外,其余各治疗组均可以降低血清IL-6含量,通阳逐瘀(7：3)组降低血清IL-6水平最为显著(P<0.01),优于通阳逐瘀(5：5)组、葱白提取物组、大黄提取物组和硝酸甘油组(P<0.05)。
与正常对照组比较,模型组大鼠心肌组织IL-6mRNA水平明显升高(P<0.05),扩增倍数为1.00；与空白模型组比较,各治疗组均可降低IL-6mRNA水平,个干预组抑制率分别为：葱白提取物组为16.49%、硝酸甘油组为27.33%、大黄提取物组为30.5%、通阳逐瘀(5：5)组为41.32%、通阳逐瘀(3：7)组为41.96%、其中通阳逐瘀(7：3)组为45.98%。
结论
①通阳逐瘀法干预急性心肌缺血的免疫机制可能与激活MAPKs及IL-6mRNA表达,影响MAPKs/IL-6信号转导通路有关。
②通阳逐瘀法通过改善心电图、提高心功能、抑制心肌酶外漏,减轻心肌损伤。
③通阳逐瘀法通过对气体信号分子H2S的调控发挥对缺血心肌的保护作用。
④通阳逐瘀不同比例组中以葱白：大黄(7：3)组疗效为优,但是由于作用环节和作用靶点的不同,药物成分的目前有些不清楚,对其整体优势的评价还有待进一步深入研究。
Research Purpose
By the comparative study of the different compatibility proportion of Chinese traditional medicine extracted from f istular onion stalk and rhubarb on the treatment of acute myocardial ischemia, the study aims to discuss the regulation effect and mechanism of blood stasis removing method on acute myocardial ischemia in rat MAPKs/IL-6signal pathway, thus preliminarily reveal the biological basis of the treatment of acute myocardial ischemia with the blood stasis removing method.
Method
This research selected64healthy pure SD male rats weighed for200-230g and aged3-4months, then they were randomly divided into normal control group, blank model group, fistular onion stalk extraction group, fistular onion stalk extraction and rhubarb extraction group of7:3,5:5,3:7, rhubarb extraction group and the nitroglycerin group, with a total8groups and8rats in each group. The acute myocardial ischemia models were prepared according to the acute myocardial ischemia model from Guo Yansong, rats were adaptively fed for1week, and were injected with3.5%sodium pentobarbital intraperitoneal (35mg/kg) for anesthesia, Rats were fixed supinely and were connected with the power lab/8s eight guided data analysis recorder, opened the chest to get records of a normal ECG, then the rats'pulses were cut to connect with the Y pulse interpolation, with the other end connected with the animal trace ventilator outlet, with a continuous inlet of10x60ml/min, and legated the left coronary artery to prepare the myocardial ischemia model, then delivered the drugs, then observed the indexes3hours later, each group was treated with the corresponding concentration of one drug, sham operation group and model group were given the same volume of saline, with a syringe5minutes after occlusion, blood collection and heart were taken4h later. Cut at the left of abdominal midline to locate the duodenum, covered the wound with saline gauze, took the blood and myocardial tissues4hours later, observed the relevant index, the drug-delivery volume was of2ml/kg, the normal control group and blank model group were given an equal volume of saline, the fistular onion stalk extraction group was delivered the drug at600mg kg-1, rhubarb extraction group at400mg kg-1, fistular onion stalk and rhubarb were mixed with the corresponding concentration of7:3,5:5,3:7in different groups, nitroglycerin group was delivered at80mg kg-1, observed for3h, and conducted ECG detection again, after observation, immediately clamped the rat thoracic wall temporarily by cl ipping the fast lines of rats, immediately took blood from the abdominal aorta and injected2ml blood into to the tube containing30UL of10%EDTA sodium and40ul of pancreatic peptide enzyme, mixed at4℃, centrifugal at3000rpm for10min, separated the plasma, and placed it in the refrigerator at-70℃for testing, the remaining blood of was centrifuged at3500rpm for20min, took the supernatant, packed and placed in the refrigerator at-70℃. Before the test, the sample was melted in cold water, mixed, and centrifuged at3500rpm for5min at4℃, then took the supernatant for testing. Recorded the electrocardiogram before and after administration, measured the average of ST segment shift and the changes of electrocardiogram of ST segment, with the standard Ⅱ electroca-rdiogram observation (standard voltage was0.1mv, paper shift speed was50mm/s). The pathological changes of rat myocardial tissues were analyzed through HE staining, the serum content of cTnl, CK-MB, LDH, IL-6were detected with ELISA assay. Chemical method was taken to detect myocardial H2S content. Western Blot method was applied for the detection of P-ERK, P-JNK, P-p38in acute myocardial ischemia in rat tissues, the real time fluorescent quantitative PCR technique was taken for the detection of IL-6mRNA expression in acute myocardial ischemia in myocardial tissues of rats; ultrasonic technology was used in the detection of cardiac function in acute myocardial ischemia rats;
Results
1. The influence on the ECG, left ventricular function and markers for myocardial infarction of acute myocardial ischemia rats:in comparison with the normal control group, the ST segment increased significantly in the blank model group (P<0.01); and the blank model group got no significant difference from the rhubarb extraction group (P>0.05), all the other treatment tissue groups could reduce rat ST segments (P<0.05, P<0.01), the effect in fistular onion stalk extraction group was the most remarkable (P<0.01), the groups of blood stasis removing method got no signi ficant difference (P>0.05).
Compared with the normal group, the serum cTnl of rats in blank model group was significantly increased (P<0.01); and serum cTnI of rats in all the treatment group were significantly decreased when compared with the blank model group (P<0.05, P<0.01), the decrease in fistular onion stalk extraction group was most obvious, and was better than any treatment group, the groups of blood stasis removing method got no significant difference (P>0.05).
Compared with the normal group, the serum CK-MB of rats in blank model group was significantly increased (P<0.01); and serum CK-MB of rats in all the treatment group were significantly decreased when compared with the blank model group (P<0.05, P<0.01), the decrease in fistular onion stalk extraction group and the nitroglycerin group was most obvious, and with no significant difference between the groups (P>0.05), the effect in fistular onion stalk extraction group was better than that in the rhubarb extraction group and the group of blood stasis removing method.
Compared with the normal group, the serum LDH of rats in blank model group was significantly increased (P<0.01); and serum LDH of rats in all the treatment group were significantly decreased when compared with the blank model group (P<0.05,P<0.01), there were no significant difference among the rhubarb extraction group, group of blood stasis removing method and the nitroglycerin group, and the effect was better than that in the fistular onion stalk extraction group, no significant differences were found in the groups of blood stasis removing method (P>0.05).
Compared with the normal group, EF, FS, Em/Am values in the model group were significantly decreased (P<0.01); compared with the model group, the EF, FS, Em/Am values in each treatment group (except the rhubarb extraction group) were significantly increased (P<0.01); as for the influence on the EF value and FS value, no significant difference was found between the group of blood stasis removing method and the group of fistular onion stalk extraction group (P>0.05), but the results were still better than that in the rhubarb extraction group and the nitroglycerin group (P<0.05); as for the influence on the Em/Am value, there were no significant differences among the groups of blood stasis removing method, or between the group of blood stasis removing method and the nitroglycerin group (P>0.05), and the effect was better than that in the fistular onion stalk extraction group.
2. Morphological influences on the rat tissues of acute myocardial ischemia The syocardial tissue sections were HE stained, and the rat myocardial cells were observed with light microscopy to find out pathological changes, the results showed that, for the normal group:most of the myocardial fibers were of normal structure, and were arranged in bundles, cardiac muscle cells were in the oval-shaped or in the shape of short spindle, they were located in the cell center and the muscle fibers scattered in the capillaries. For the model group:myocardial fiber was swelling, part of the myocardial fiber fracture was found, small focal muscle fiber necrosis was noticed, and the muscle fiber structure was unclear; muscle fiber capillary was dilatated and congested, and focal infiltration of inflammatory cells was found. Most of the myocardial fiber structure of the fistular onion stalk extraction group was normal, and only a small number of muscle fiber swelling was found, which were arranged in bundles, the muscle fibers were scattered in the capillaries, and no focal necrosis was found. The groups of blood stasis removing method (7:3), in this group, part of the myocardial fiber structure was normal, a small number of muscle fiber swelling was detected, capillaries between the muscle fibers increased. In the rest of the treatment groups, focal myocardial swelling was found, with blurred structure, and part of the myocardial fiber was broken, and telangiectasia was found in a few capillaries of muscle fibers.
3. Influence on the myocardial tissue of H2S of rats with acute myocardial ischemia Compared with the normal control group, the H2S decreased significantly in the blank model group (P<0.01); and the H2S level of each treatment group was significantly increase-ed when compared wi th the blank model group (P<0.01), the increase was most obvious in the group of blood stasis removing method (7:3), and the results were significantly better than that in the fistular onion stalk extraction group, rhubarb extraction group, the nitroglycerin group and other groups of blood stasis removing method.
4. The influence on MAPKs of rats with acute myocardial ischemia
Compared with the normal control group, the P-ERK expression in model group was significantly increased (22.54%), suggesting a successful modeling. Compared with the model group, except for the group of blood stasis removing method (7:3)(P>0.05), P-ERK was significantly decreased in the other treatment groups, the inhibitory rate of each intervention group were:6.29%in the group of blood stasis removing method (5:5),8.94%in the nitroglycerin group,9.05%in the fistular onion stalk extraction group,11.17%in the rhubarb extraction group, and it was13.34%in the group of blood stasis removing method (3:7).
Compared with the normal control group, the P-JNK protein expression in model group was significantly increased (44.58%), suggesting a successful modeling. Compared with the model group, the P-ERK was significantly decreased in each treatment group, and the inhibitory rate of each intervention group were:14.17%in the group of blood stasis removing method (3:7),24.83%in the group of blood stasis removing method (5:5),25.59%in the rhubarb extraction group,26.37%in the fistular onion stalk extraction group,26.56%in the nitroglycerin group, and31.73%in the group of blood stasis removing method (7:3).
Compared with the normal control group, the P-p38protein expression in model group was significantly increased (88.0%), suggesting a successful modeling. Compared with the model group, the P-P38expression was significantly decreased in each treatment group, and the inhibitory rate of each intervention group were:18.91%in the rhubarb extraction group,24.31%in the group of blood stasis removing method (3:7),31.64%in the group of blood stasis removing method (5:5),44.20%in the fistular onion stalk extraction group,45.25%in the group of blood stasis removing method (7:3) and45.29%in the nitroglycerin group.
5. The influence on myocardial tissue IL-6of rats with acute myocardial ischema Compared with the normal control group, the IL-6level of rats in model group was significantly increased (P<0.01), compared with the model group, except for the group of blood stasis removing method (3:7)(P>0.05), all the other treatment groups could decrease the level of serum IL-6, and the decrease of serum IL-6was most significant in the group of blood stasis removing method (7:3)(P<0.01), which was better than that in the group of blood stasis removing method(5:5), the rhubarb extraction group, the fistular onion stalk extraction group and the nitroglycerin group (P<0.05).
Compared with the normal control group, the IL-6mRNA level of heart muscle tissue of rats in model group was significantly increased (P<0.05), with the amplification of1.00; compared with the blank model group, all the treatment groups can reduce the level of IL-6mRNA, and the inhibition rate of each intervention group was:16.49%in the fistular onion stalk extraction group,27.33%in the nitroglycerin group,30.5%in the rhubarb extraction group,41.32%in the group of blood stasis removing method (5:5),41.96%in the group of blood stasis removing method (3:7), and45.98%in the group of blood stasis removing method (7:3)
Conclusion
1. The immune mechanisms of the blood stasis removing method intervening acute myocardial ischemia may be related with the activation of MAPKs and IL-6mRNA expression and the influence on MAPKs/IL-6signal transduction pathway.
2. The blood stasis removing method could inhibit myocardial enzyme leakage and reduce myocardial injury by improving ECG, and enhancing the cardiac function.
3. The blood stasis removing method protects the ischemic myocardium through the regulation of gaseous molecules of H2S.
4. Of the different proportions of blood stasis removing, the group of scallion stalk with rhubarb (7:3) got the best efficacy, but due to the differences of the action segments and targets, and the unclear drug ingredients, further studies on the evaluation of its overall advantage are still in need.
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