天然冰片组方的抗心肌缺血作用及量效关系研究

【作者】 王怡；

【导师】 张伯礼；

【作者基本信息】 天津中医学院 ， 中医内科学， 2002， 硕士

【摘要】 垂体后叶素(Pituitrin，Pit)诱发大鼠急性心肌缺血是筛选抗心肌缺血药物的简便实用模型之一。为克服动物对Pit敏感性偏倚，提高药物评价的可靠性，本文对该模型制备方法进行了改进，并以心电图、心肌酶、氧自由基的变化为评价指标，比较了天然冰片和合成冰片组成的复方丹参滴丸药效，以及天然冰片不同剂量(1mg、7.5mg、10mg、15mg、30mg／30粒滴丸)对复方丹参滴丸药效的影响，同时观察了丹参、三七药对不同组方抗心肌缺血的药效差异，另外采用大鼠小鼠灌胃和腹腔注射两种给药途径比较了两种冰片的急性毒性。1．垂体后叶素诱发大鼠急性心肌缺血模型制备方法和评价指标的改进 选用Pit敏感大鼠用于实验，改鼠尾静脉注射Pit为舌下静脉注射，改观察心肌缺血的阳性率为观察注射Pit后不同时间点心电图的变化，将观察时间延长至3小时，同时比较了两种剂量Pit(0.75~u╱kg和0.35~u／kg)诱发的心肌缺血变化，结果：大鼠注射0.75~u／kg的Pit比注射0.35~u／kg缺血程度重，主要表现注射后第一期心电图T波的变化，Pit的剂量大(0.75~u／kg)，T波变化大(70.14％)，Pit的剂量小(0.35~u／kg)，T波变化小(43.58％)，两种变化差异显著(P〈0.01)；两种剂量均可使注射Pit后3小时心电图T波显著抬高(变化率分别为87.64％、81.53％)，提示可能存在心肌缺血再灌注损伤。2．天然冰片和合成冰片组成的复方丹参滴丸抗垂体后叶素致大鼠急性心肌缺血的药效比较研究 大鼠注射0.75~u／kgPit后即刻出现心电图T波显著抬高，15秒达高峰，与注射前比较T波增长70.14％，于注射Pit后6-9分钟T波再次升高，T波增长53.87％，3小时T波增长81.53％，两种冰片组成的复方丹参滴丸均能抗 — —Pit引起的心电图T波抬高，与模型组比较差异有显著意义u功．01）；两种复方丹参滴丸用药组的心电图恢复正常例数比模型组有增加趋势。 ． 模型组血清和心肌SOD活性显著降低，u含量显著升高，与正常对照组比较差异有显著意义门删．01）；应用两种复方丹参滴丸治疗后均能显著提高 SOD活性、降低MI）A含量，与模型组比较差异有显著意义汗q．01）；两种．复方丹参滴丸组具有降低血清CPK、LDH含量的作用。3．不同剂量天然冰片组成的复方丹参滴丸抗垂体后叶素致大鼠急性心肌咖 的药效比刎究 模型组大鼠注射0．35丫kgPit后即刻出现T波抬高，30秒达高峰，与注射前比较T栅长43．58儿 于注射Pit后6刁分钟T波再次升高，T波增长44．07儿3 ／J’时T波增长87．64儿不同时问点的心电图恢复正常例数明显减少；五种剂量天然冰片组成的复方丹参滴丸组均能抗 Pi t引起的心电图变化，与模型组比较差异有显著言义吓叩．01）。 血清及心肌SOD、MDA含量的变化与上述买验变化规律基太相同．各复万丹参－高丸组均能显著提高SOD活性，降低＼IDA含量，与莫型组比较羞异有显著意义n＜0．01）；复方丹参涌丸组（分别含天然冰片的剂量勺 1伽g、15mg、30mg门0粒滴丸），可降低血清 LDH含量，与模型组比较差异有显著意义（P的．01），对血清叩K无明显降低作用。4．不同组分构成的复方丹参方抗垂体后叶素致大鼠急性心肌晌的药效比较 ． 研究S 模型组大鼠庄射 0．35‘八g Pi t后心电图、氧自由基、心肌酶的变化规律与上述买验相同。复方丹参滴丸（丹参、三七、冰片）、黄蔑丹参滴丸（黄蔑、＠ l丹参、三七、降香油）、冠。G丹参滴丸（丹参、三七、降香油）均具有抗pit诱发大鼠，心肌缺血的作用，且三方之间的药效无显著差异，但黄芭丹参滴丸！ 155 — — 组在改善心电图方面有优于另外两种组方的趋势。 5．天然冰片与合成冰片的急性毒性比舰究巴 小鼠、大鼠给予天然冰片和合成冰片后主要中毒症状均为兴奋、行走不 稳，严重者腹卧不动、?更多还原

【Abstract】 The acute myocardial ischemic (AMI) pituitrin (Pit)-induced is one of the models in selecting anti-AMI drugs. In order to avoid the different responses of Pit and enhance the reliabilities of evaluing the medical effects, the establishment of AMI methods have been improved in this experiment. By observing the effects on electrocardiograph (ECG), cardiac muscle enzyme (LDH,CPK) and oxygen free radical (OFR), the effects of different prescriptions of nature borneol and the relations of dosages and effects on AMI were observed. We comparatively study the pharmacodynamic variabilities of compound danshen drop pill (CDSP) composed of synthetic bomeol or nature bomeol, and five kinds of CDSP with different dosages of nature bomeol (Img, 7.5mg, lOmg, 15mg, 30mg/30grain drop pill) and three kinds of FFDSF (fufang danshen fang) on Pit-induced AMI. The difference of acute toxicity of synthesize borneol and nature bomeol was observed by ip and ig to rats and mice.1. The improvement on methods of making Pit- induced AMI model and parameter for elevating.First, the Pit-sensitive rais were selected, and the Pit was injected via sublingual vein instead of trail vein, and the observing time was prolonged to 3 hours. The models induced by two different dosages of Pit (0.75u/kg and 0.35u/kg) were observed comparatively. The results showed that: the degree of MI was more significant by injecting 0.75u/kg Pit than that of 0.35u/kg. The main representation was the changes of T-wave on the first period of ECG. The higher dosages(0.75u/kg )of Pit, the more changes of T-wave (70.14%), the lower dosages(0.35u/kg),the less changes (43.58%),the diflrence was significant. The ECG of both dosages after injecting Pit 3 hours showed that the T-wave all ran up significantly (87.64%,81.53% respectively) and the ischemic reperfusion(IR) maybe exist.2. Comparatively study the pharmacodynamic variabilities ofCDSP composed of nature borneol or synthetic borneol on Pit -induced AMI in rats.After injecting Pit at 0.75u/kg to model group,the T-wave on ECG ran up immediately and reached the maximal heights which increased 70.14% at 15 second compared to that of before injecting Pit. The T-wave ran up again increasing 53.87% at 6-9minute and 81.53% at 3 hours. Two kinds of CDSP composed of nature borneol and synthestic borneol both had the functions of decreasing the heights of T-wave. The difference was significant compared with model group(P<0.01). The recoveries number of the groups treated with CDSP were more than that of model group.The activities of SOD in serum and cardiac muscle decreased and the contents of MDA increased in model group. The difference was significant compared with normal group(P<0.01). After treated with two kinds of CDSP, the activities of SOD increased and the contents of MDA decreased, the difference was significant compared with model group(P<0.01). The contents of LDH or CPK can also be reduced3. Comparatively study the pharmacodynamic variabilities of CDSP composed of different dosages of nature borneol on Pit -induced AMIAfter injecting Pit at 0.35u/kg to model group, the T-wave on ECG ran up immediately and reach the maximal heights which increased 43.58% at 30 second compared to that of before injecting Pit. The T-wave ran up again increasing 44.07% at 6-9minute and 87.64% at 3 hours. The recoveries number at different time points after injecting Pit were less than CDSP groups. Five kinds of CDSP composed of different dosages of nature borneol all had the functions of decreasing the heights of T-wave,but the difference had not been found.The difference was significant compared with model group(P<0.01).The changes of activities of SOD and the contents of MDA in serum and cardiac muscle related to above test. After treated with five kinds of CDSP, the activities of SOD increase and the contents of MDA deceased. The difference was significant compared with model group(P<0.01). CDSP groups composed of naturebomeol(10mg> 15mg^ 30mg/30 pills) could decrease the contents of LDH in ser更多还原