冠心Ⅱ号心脏保护作用的物质基础及其舒张大鼠胸主动脉机制的研究
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摘要
背景：方剂是中医临床治疗疾病的主要工具与手段,其临床疗效经过几千年的实践已毋庸置疑。但是是什么活性成分产生了方剂疗效作用,机制是什么,该问题一直是长期存在的重大问题,也是制约中医药现代化的瓶颈。本课题拟采用BAP策略研究冠心Ⅱ的心脏保护作用的物质基础和其舒张大鼠胸主动脉环的机制,从而解决这长期困扰中医药学术界的难题。
1冠心Ⅱ心脏保护作用的物质基础研究回顾
目的：回顾冠心Ⅱ号和其吸收活性物质FTAPE单独和联合应用对大鼠的心脏保护作用。方法：利用我课题组资料,采用结扎左冠状动脉前降支法建立大鼠急性心肌梗死模型。用HPLC测得冠心Ⅱ号的五种主要成分含量(mg/g)如下：丹参素：0.936±0.013；阿魏酸：0.169±0.004；羟基红花黄色素A：2.591±0.021；原儿茶醛0.018±0.001(P)；芍药苷3.715±0.123(E)。FTAPE单独和联合应用和母方疗效比较。结果：将FTA混合物与母方疗效比较,FAT剂量等于母方中含量两者心脏保护作用疗效类似。结论：冠心Ⅱ号的心脏保护作用是由吸收的FTA三成分引起的。
2丹参素舒张大鼠胸主动脉机制研究
目的：明确丹参素对大鼠离体血管环张力的影响,探讨其具体机制。
方法：采用大鼠离体胸主动脉灌流技术,以累积浓度法观测丹参素(10-1M～10-6M)对基础状态、苯丙肾上腺素(1μmol/L)和氯化钾KCl(60mmol/L)预收缩的血管环张力的影响；运用一氧化氮合酶抑制剂N-硝基-L-精氨酸甲酯(10μmol/L)、鸟苷酸环化酶抑制剂亚甲蓝(10μmol/L)环氧合酶抑制剂吲哚美辛(10μmol/L)处理血管环,探讨影响血管环张力的机制。结果：对基础状态或氯化钾(60mmol/L)预收缩的血管环无影响,而对苯丙肾上腺素(1μmol/L)预收缩的内皮完整血管环产生浓度依赖性的舒张作用,并且去除内皮后的舒张作用被取消。用N-硝基-L-精氨酸甲酯(10μmol/L)和亚甲蓝(10μmol/L)预处理后,均可阻断的舒张血管作用,而用吲哚美辛(10μmol/L)预处理后未能阻断的血管舒张作用。结论：丹参素(T)(10-1M～10-6M)通过NO-sGC-cGMP途径产生内皮依赖的血管舒张作用。
3阿魏酸舒张大鼠胸主动脉机制研究
目的：明确阿魏酸对大鼠离体血管环张力的影响,探讨其具体机制。方法：采用大鼠离体胸主动脉灌流技术,以累积浓度法观测阿魏酸(10-1mM～103mM)对基础状态、苯丙肾上腺素(1μmol/L)和氯化钾(60mmol/L)预收缩的血管环张力的影响；在无钙K-H液中,以累积浓度法观测阿魏酸(10-1mM～103mM)对苯丙肾上腺素和咖啡因预收缩的血管环张力的影响；分别运用钾通道阻断剂四乙胺(10mmol/L)、格列本脲(10μmol/L)、氯化钡(1mmol/L)、4-氨基吡啶(1mmol/L)处理血管环,探讨影响血管环张力的机制。结果：对基础状态或氯化钾(60mmol/L)预收缩的血管环无影响,而对苯丙肾上腺素(1μmol/L)预收缩的内皮完整和去内皮的血管环产生浓度依赖性的舒张作用,并且去除内皮后的舒张作用未受影响。在无钙K-H液中,可舒张咖啡因(20mol/L)预收缩的血管环。格列本脲可部分阻断阿魏酸(10-1mM～103mM)舒张血管环的作用。结论：我们最终认为阿魏酸(F)(10-1mM～103mM)舒张血管环的机制是非内皮依赖性的,是通过阻滞ROC进一步抑制细胞内肌浆网中ryanodine或咖啡因敏感钙池的Ca2+释放和一定程度上是通过开放ATP敏感性钾通道(ATP-Sensitive potassium channel, KATP)而实现的。
4羟基红花黄色素A舒张大鼠胸主动脉机制研究
目的：明确羟基红花黄色素A对大鼠离体血管环张力的影响,探讨其具体机制。方法：采用大鼠离体胸主动脉灌流技术,以累积浓度法观测羟基红花黄色素A(10-1M-10-6M)对基础状态、苯丙肾上腺素(1μmol/L)和氯化钾(60mmol/L)预收缩的血管环张力的影响；运用一氧化氮合酶抑制剂N-硝基-L-精氨酸一酯环氧合酶抑制剂环氧合酶抑制剂吲哚美辛处理血管环；在无钙K-H液中,以累积浓度法观测阿魏酸对苯丙肾上腺素(1μmol/L)和咖啡因(20mol/L)预收缩的血管环张力的影响；另外分别运用钾通道阻断剂四乙胺(10mmol/L)、格列本脲(10μmol/L)、氯化钡(1mmol/L)、4-氨基吡啶(1mmol/L)处理血管环,探讨影响血管环张力的机制。结果：对基础状态预收缩的血管环无影响,而对氯化钾和苯丙肾上腺素预收缩的内皮完整血管环产生浓度依赖性的舒张作用,并且去除内皮后的舒张作用被部分抑制。用左吲哚美辛(10μmol/L)预处理后,可部分阻断的舒张血管作用,而用N-硝基-L-精氨酸甲酯(10μmol/L)预处理后未能阻断的血管舒张作用。在无钙K-H液中,可舒张苯丙肾上腺预收缩的血管环。4-氨基吡啶(1mmol/L)可部分阻断阿魏酸舒张血管环的作用。结论：综上所述,我们最终认为羟基红花黄色素A(A)(10-1M-10-6M)舒张血管环的机制是内皮依赖性和非内皮依赖性两种机制共同作用的结果。其中内皮依赖性舒张机制是通过前列腺素类物质的产生与特异性受体结合后发挥扩张血管的作用；非内皮依赖性是通过通过阻滞ROC和VOC进一步抑制细胞内IP3敏感Ca2+通道的开放和一定程度上是通过开放电压依赖型钾通道(voltage dependent potassium channel, Kv)而实现的。
总结：冠心Ⅱ号有多靶点的心脏保护作用,我们证明FTA是心脏保护的药效学物质基础；FTA做为冠心Ⅱ号体内通过扩张血管增加MBF的药效学基础,三者的机制联合应该做为冠心Ⅱ号舒张血管增加MBF的综合机制,即：内皮依赖性通过增加内皮产生NO(NO-sGC-cGMP途径)和前列腺素类物质舒张血管；非内皮依赖性是通过阻断VOC和ROC减少细胞外Ca2+内流、抑制细胞内ryanodine或咖啡因敏感钙池的Ca2+和IP3敏感Ca2+通道的开放和开放KATP,KV等机制的联合作用。
BACKGROUND:The main form of Traditional Chinese Medicine (TCM) is composite prescription. Its therapeutic effects are confirmed after over thousand years clinical practice. It remains largely a secret that which and how active constituents of composite prescription produce the effectiveness, which has now become a main bottleneck restricting the TCM modernizations. We will study the cardioprotective effect of Guanxin II substance basis and its vasodilative effect and mechanism on thoracic aorta of rats with bioethnopharmaceutical analytical phannacology and solve the problem which has puzzled TCM for so long time。
I Review the research on the cardioprotective effect of Guanxin II substance basis
Objective To review the cardioprotective effects of GXII and FATPE, alone and in combination, and of some components of FATPE in AMI rat. Method Using my task group material, SD rats with acute myocardial infarction (AMI) were induced by coronary occlusion.The contents of the five components including ferulic acid (0.169±0.004), tanshinol (0.936±0.013), hydroxyl safflor yellow A (2.591±0.021), protocatechualdehyde (0.018±0.001) and Paeoniflorin (3.715±0.123) in the formula were determined by high-performance liquid chromatography (HPLC) method respectively. Compare the cardioprotect effects of GXII and FATPE, alone and in combination, and of some components of FATPE in AMI rat. Result Comparing the mixture of FTA and original formula, FAT(dose=amount of the original formula) was similar to GXII in cardioprotective effects. Conclusion The cardioprotective effect substance basis of Guanxin II is FTA.
II Reasearch on vasodilative effect and mechanism of Tanshinol in thoracic aorta of rats
Objective The aim was to study Tanshinol(10-1M～10-6M) in isolated rat thoracic aortic ring vasodilative effect and its mechanisms. Method Isometric tension was recorded in response to drugs in organ bath. Effects of Tanshinol(10-1M～10-6M) on the vascular tone of resting, high KCl(60mmol/L) and PE(1μmol/L) pre-constricted rat thoracic aorta with or without endothelium were determined. To explore the mechanism, nitric oxide synthase inhibitor L-NAME(10μmol/L), guanylyl cyclase inhibitor methyline blue MB(10μmol/L), cyclooxygenase inhibitor indomethacin(10μmol/L) were ued. Result No vasomotor response to accumulated Tanshinol(10-1M～10-6M) were recorded in both resting and KCl-depolarized rings Tanshinol(10-1M～10-6M) caused concentration relaxation of aorta rings preconstricted with PE(1μmol/L) in endothelium-intact rings. Removal of the endothelium, or pretreated with L-NAME(10μmol/L) or MB(10μmol/L) inhibited the relaxation of Tanshinol(10-1M～10-6M). Pretreatment with Indo (10μmol/L) could not abolish the relaxation response to Tanshinol.
Conclusion The results indicated that the relaxation by Tanshinol(10-1M～10-6M) in rat aorta ring is endothelium dependent and is possibly mediated by the NO-sGC-cGMP pathway.
Ⅲ Reasearch on vasodilative effect and mechanism of Ferulic acid in thoracic aorta of rats
Objective The aim was to study Ferulic acid(10-1mM～103mM) in isolated rat thoracic aortic ring vasodilative effect and its mechanisms. Method Isometric tension was recorded in response to drugs in organ bath. Effects of Ferulic acid(10-1mM～103mM) on the vascular tone of resting, high KCl(60mmol/L) and PE(1μmol/L) pre-constricted rat thoracic aorta with or without endothelium were determined. In some experiments, Effects of Ferulic acid(10-1mM～103mM) on the vascular tone of PE(1μmol/L)and Caf(20mol/L) pre-constricted rat thoracic aorta in Ca2+-free K-H solution were also determined. To explore the further mechanism on K+channels, ATP-Sensitive potassium channel inhibitor Gli(10μmol/L), inward rectifier potassium channel BaCl2(lmmol/L), calcium activated potassium channel TEA(10mmol/L), voltage dependent potassium channel4-AP(1mmol/L) were also used. Result No vasomotor response to accumulated Ferulic acid(10-1mM～103mM) were recorded in both resting and KCl-depolarized rings. Ferulic acid (10-1mM～103mM) caused concentration relaxation of aorta rings preconstricted with PE(1μmol/L) in endothelium-intact rings. Removal of the endothelium, or pretreated with L-NAME(10μmol/L) did not inhibite the relaxation of Ferulic acid(10-1mM～103mM). Pretreatment with Indo(10μmol/L) could not abolish the relaxation response to Ferulic acid(10-1mM～103mM). In Ca2+-free K-H solution, Ferulic acid(10-1mM～103mM) could relax Caf-constricted rat thoracic aorta. Gli(10μmol/L) could partly abolish the relaxation response to Ferulic acid. Conclusion The results indicated that the relaxation by Ferulic acid(10-1mM～103mM) in rat aorta ring is endothelium independent and is possibly mediated by blocking ROC and furtherly inhibiting ryanodine or caffeine sensitive calcium release, partly open ATP-Sensitive potassium channel.
IV Reasearch on vasodilative effect and mechanism of hydroxyl safflor yellow A in thoracic aorta of rats
Objective The aim was to study hydroxyl safflor yellow A(10-6M～10-1M) in isolated rat thoracic aortic ring vasodilative effect and its mechanisms. Method Isometric tension was recorded in response to drugs in organ bath. Effects of hydroxyl safflor yellow A on the vascular tone of resting, high KCl(60mmol/L) and PE(1μmol/L) pre-constricted rat thoracic aorta with or without endothelium were determined. To explore the mechanism, nitric oxide synthase inhibitor L-NAME and cyclooxygenase inhibitor indomethacin were ued. In some experiments, Effects of hydroxyl safflor yellow A(10-6M～10-1M) on the vascular tone of PE(1μmol/L)and Caf(20mol/L) pre-constricted rat thoracic aorta in Ca2+-free K-H solution were also determined. To explore the further mechanism on K+channels, ATP-Sensitive potassium channel inhibitor Gli(10μmol/L), inward rectifier potassium channel BaCl2(lmmol/L), calcium activated potassium channel TEA(1Ommol/L), voltage dependent potassium channel4-AP(1mmol/L) were also used. Result No vasomotor response to accumulated hydroxyl safflor yellow A were recorded in both resting and KCl-depolarized rings. Hydroxyl safflor yellow A(10-6M～10-1M) caused concentration relaxation of aorta rings preconstricted with PE(1μmol/L) in endothelium-intact rings. Removal of the endothelium, or pretreated with Indo could partly inhibite the relaxation of hydroxyl safflor yellow A(10-6M～10-1M). Pretreatment with L-NAME(10μmol/L) could not abolish the relaxation response to hydroxyl safflor yellow A(10-6M～10-1M). In Ca2+-free K-H solution, hydroxyl safflor yellow A(106M～10-1M) could relax PE-constricted rat thoracic aorta.4-AP could partly abolish the relaxation response to hydroxyl safflor yellow A(10-6M～10-1M). Conclusion In conclusion, hydroxyl safflor yellow A(106M～10-1M) relaxed rat aorta rings through blocking ROC, VOC and furtherly inhibiting IP3sensitive calcium release, partly open voltage dependent potassium channel. The endothelium-dependent vessel dilation of hydroxyl safflor yellow A(10-6M～10-1M) was attributed mainly to the endothelium-dependent cyclooxygenase pathway.
Conclusion GXII is multi-target therapy in cardioprotective effect, and FTA was proved to be the pharmacodynamics substance basis. FAT was similar to GXII in increasing MBF. The combination mechanisms of FTA is the GX II vasodilative mechanism. GXII relaxed thoracic aorta of rats through blocking calcium influx and intracellular calcium release extracellularly, inhibiting Ca2+release in IP3, ryanodine or Caffeine sensitive calcium pool intracellularly and mediating by opening of ATP-dependent potassium channels and voltage dependent potassium channel. The endothelium-dependent vessel dilation of GXII was attributed mainly to the endothelium-dependent NO-sGC-cGMP and cyclooxygenase pathway.
1冠心Ⅱ心脏保护作用的物质基础研究回顾
目的：回顾冠心Ⅱ号和其吸收活性物质FTAPE单独和联合应用对大鼠的心脏保护作用。方法：利用我课题组资料,采用结扎左冠状动脉前降支法建立大鼠急性心肌梗死模型。用HPLC测得冠心Ⅱ号的五种主要成分含量(mg/g)如下：丹参素：0.936±0.013；阿魏酸：0.169±0.004；羟基红花黄色素A：2.591±0.021；原儿茶醛0.018±0.001(P)；芍药苷3.715±0.123(E)。FTAPE单独和联合应用和母方疗效比较。结果：将FTA混合物与母方疗效比较,FAT剂量等于母方中含量两者心脏保护作用疗效类似。结论：冠心Ⅱ号的心脏保护作用是由吸收的FTA三成分引起的。
2丹参素舒张大鼠胸主动脉机制研究
目的：明确丹参素对大鼠离体血管环张力的影响,探讨其具体机制。
方法：采用大鼠离体胸主动脉灌流技术,以累积浓度法观测丹参素(10-1M～10-6M)对基础状态、苯丙肾上腺素(1μmol/L)和氯化钾KCl(60mmol/L)预收缩的血管环张力的影响；运用一氧化氮合酶抑制剂N-硝基-L-精氨酸甲酯(10μmol/L)、鸟苷酸环化酶抑制剂亚甲蓝(10μmol/L)环氧合酶抑制剂吲哚美辛(10μmol/L)处理血管环,探讨影响血管环张力的机制。结果：对基础状态或氯化钾(60mmol/L)预收缩的血管环无影响,而对苯丙肾上腺素(1μmol/L)预收缩的内皮完整血管环产生浓度依赖性的舒张作用,并且去除内皮后的舒张作用被取消。用N-硝基-L-精氨酸甲酯(10μmol/L)和亚甲蓝(10μmol/L)预处理后,均可阻断的舒张血管作用,而用吲哚美辛(10μmol/L)预处理后未能阻断的血管舒张作用。结论：丹参素(T)(10-1M～10-6M)通过NO-sGC-cGMP途径产生内皮依赖的血管舒张作用。
3阿魏酸舒张大鼠胸主动脉机制研究
目的：明确阿魏酸对大鼠离体血管环张力的影响,探讨其具体机制。方法：采用大鼠离体胸主动脉灌流技术,以累积浓度法观测阿魏酸(10-1mM～103mM)对基础状态、苯丙肾上腺素(1μmol/L)和氯化钾(60mmol/L)预收缩的血管环张力的影响；在无钙K-H液中,以累积浓度法观测阿魏酸(10-1mM～103mM)对苯丙肾上腺素和咖啡因预收缩的血管环张力的影响；分别运用钾通道阻断剂四乙胺(10mmol/L)、格列本脲(10μmol/L)、氯化钡(1mmol/L)、4-氨基吡啶(1mmol/L)处理血管环,探讨影响血管环张力的机制。结果：对基础状态或氯化钾(60mmol/L)预收缩的血管环无影响,而对苯丙肾上腺素(1μmol/L)预收缩的内皮完整和去内皮的血管环产生浓度依赖性的舒张作用,并且去除内皮后的舒张作用未受影响。在无钙K-H液中,可舒张咖啡因(20mol/L)预收缩的血管环。格列本脲可部分阻断阿魏酸(10-1mM～103mM)舒张血管环的作用。结论：我们最终认为阿魏酸(F)(10-1mM～103mM)舒张血管环的机制是非内皮依赖性的,是通过阻滞ROC进一步抑制细胞内肌浆网中ryanodine或咖啡因敏感钙池的Ca2+释放和一定程度上是通过开放ATP敏感性钾通道(ATP-Sensitive potassium channel, KATP)而实现的。
4羟基红花黄色素A舒张大鼠胸主动脉机制研究
目的：明确羟基红花黄色素A对大鼠离体血管环张力的影响,探讨其具体机制。方法：采用大鼠离体胸主动脉灌流技术,以累积浓度法观测羟基红花黄色素A(10-1M-10-6M)对基础状态、苯丙肾上腺素(1μmol/L)和氯化钾(60mmol/L)预收缩的血管环张力的影响；运用一氧化氮合酶抑制剂N-硝基-L-精氨酸一酯环氧合酶抑制剂环氧合酶抑制剂吲哚美辛处理血管环；在无钙K-H液中,以累积浓度法观测阿魏酸对苯丙肾上腺素(1μmol/L)和咖啡因(20mol/L)预收缩的血管环张力的影响；另外分别运用钾通道阻断剂四乙胺(10mmol/L)、格列本脲(10μmol/L)、氯化钡(1mmol/L)、4-氨基吡啶(1mmol/L)处理血管环,探讨影响血管环张力的机制。结果：对基础状态预收缩的血管环无影响,而对氯化钾和苯丙肾上腺素预收缩的内皮完整血管环产生浓度依赖性的舒张作用,并且去除内皮后的舒张作用被部分抑制。用左吲哚美辛(10μmol/L)预处理后,可部分阻断的舒张血管作用,而用N-硝基-L-精氨酸甲酯(10μmol/L)预处理后未能阻断的血管舒张作用。在无钙K-H液中,可舒张苯丙肾上腺预收缩的血管环。4-氨基吡啶(1mmol/L)可部分阻断阿魏酸舒张血管环的作用。结论：综上所述,我们最终认为羟基红花黄色素A(A)(10-1M-10-6M)舒张血管环的机制是内皮依赖性和非内皮依赖性两种机制共同作用的结果。其中内皮依赖性舒张机制是通过前列腺素类物质的产生与特异性受体结合后发挥扩张血管的作用；非内皮依赖性是通过通过阻滞ROC和VOC进一步抑制细胞内IP3敏感Ca2+通道的开放和一定程度上是通过开放电压依赖型钾通道(voltage dependent potassium channel, Kv)而实现的。
总结：冠心Ⅱ号有多靶点的心脏保护作用,我们证明FTA是心脏保护的药效学物质基础；FTA做为冠心Ⅱ号体内通过扩张血管增加MBF的药效学基础,三者的机制联合应该做为冠心Ⅱ号舒张血管增加MBF的综合机制,即：内皮依赖性通过增加内皮产生NO(NO-sGC-cGMP途径)和前列腺素类物质舒张血管；非内皮依赖性是通过阻断VOC和ROC减少细胞外Ca2+内流、抑制细胞内ryanodine或咖啡因敏感钙池的Ca2+和IP3敏感Ca2+通道的开放和开放KATP,KV等机制的联合作用。
BACKGROUND:The main form of Traditional Chinese Medicine (TCM) is composite prescription. Its therapeutic effects are confirmed after over thousand years clinical practice. It remains largely a secret that which and how active constituents of composite prescription produce the effectiveness, which has now become a main bottleneck restricting the TCM modernizations. We will study the cardioprotective effect of Guanxin II substance basis and its vasodilative effect and mechanism on thoracic aorta of rats with bioethnopharmaceutical analytical phannacology and solve the problem which has puzzled TCM for so long time。
I Review the research on the cardioprotective effect of Guanxin II substance basis
Objective To review the cardioprotective effects of GXII and FATPE, alone and in combination, and of some components of FATPE in AMI rat. Method Using my task group material, SD rats with acute myocardial infarction (AMI) were induced by coronary occlusion.The contents of the five components including ferulic acid (0.169±0.004), tanshinol (0.936±0.013), hydroxyl safflor yellow A (2.591±0.021), protocatechualdehyde (0.018±0.001) and Paeoniflorin (3.715±0.123) in the formula were determined by high-performance liquid chromatography (HPLC) method respectively. Compare the cardioprotect effects of GXII and FATPE, alone and in combination, and of some components of FATPE in AMI rat. Result Comparing the mixture of FTA and original formula, FAT(dose=amount of the original formula) was similar to GXII in cardioprotective effects. Conclusion The cardioprotective effect substance basis of Guanxin II is FTA.
II Reasearch on vasodilative effect and mechanism of Tanshinol in thoracic aorta of rats
Objective The aim was to study Tanshinol(10-1M～10-6M) in isolated rat thoracic aortic ring vasodilative effect and its mechanisms. Method Isometric tension was recorded in response to drugs in organ bath. Effects of Tanshinol(10-1M～10-6M) on the vascular tone of resting, high KCl(60mmol/L) and PE(1μmol/L) pre-constricted rat thoracic aorta with or without endothelium were determined. To explore the mechanism, nitric oxide synthase inhibitor L-NAME(10μmol/L), guanylyl cyclase inhibitor methyline blue MB(10μmol/L), cyclooxygenase inhibitor indomethacin(10μmol/L) were ued. Result No vasomotor response to accumulated Tanshinol(10-1M～10-6M) were recorded in both resting and KCl-depolarized rings Tanshinol(10-1M～10-6M) caused concentration relaxation of aorta rings preconstricted with PE(1μmol/L) in endothelium-intact rings. Removal of the endothelium, or pretreated with L-NAME(10μmol/L) or MB(10μmol/L) inhibited the relaxation of Tanshinol(10-1M～10-6M). Pretreatment with Indo (10μmol/L) could not abolish the relaxation response to Tanshinol.
Conclusion The results indicated that the relaxation by Tanshinol(10-1M～10-6M) in rat aorta ring is endothelium dependent and is possibly mediated by the NO-sGC-cGMP pathway.
Ⅲ Reasearch on vasodilative effect and mechanism of Ferulic acid in thoracic aorta of rats
Objective The aim was to study Ferulic acid(10-1mM～103mM) in isolated rat thoracic aortic ring vasodilative effect and its mechanisms. Method Isometric tension was recorded in response to drugs in organ bath. Effects of Ferulic acid(10-1mM～103mM) on the vascular tone of resting, high KCl(60mmol/L) and PE(1μmol/L) pre-constricted rat thoracic aorta with or without endothelium were determined. In some experiments, Effects of Ferulic acid(10-1mM～103mM) on the vascular tone of PE(1μmol/L)and Caf(20mol/L) pre-constricted rat thoracic aorta in Ca2+-free K-H solution were also determined. To explore the further mechanism on K+channels, ATP-Sensitive potassium channel inhibitor Gli(10μmol/L), inward rectifier potassium channel BaCl2(lmmol/L), calcium activated potassium channel TEA(10mmol/L), voltage dependent potassium channel4-AP(1mmol/L) were also used. Result No vasomotor response to accumulated Ferulic acid(10-1mM～103mM) were recorded in both resting and KCl-depolarized rings. Ferulic acid (10-1mM～103mM) caused concentration relaxation of aorta rings preconstricted with PE(1μmol/L) in endothelium-intact rings. Removal of the endothelium, or pretreated with L-NAME(10μmol/L) did not inhibite the relaxation of Ferulic acid(10-1mM～103mM). Pretreatment with Indo(10μmol/L) could not abolish the relaxation response to Ferulic acid(10-1mM～103mM). In Ca2+-free K-H solution, Ferulic acid(10-1mM～103mM) could relax Caf-constricted rat thoracic aorta. Gli(10μmol/L) could partly abolish the relaxation response to Ferulic acid. Conclusion The results indicated that the relaxation by Ferulic acid(10-1mM～103mM) in rat aorta ring is endothelium independent and is possibly mediated by blocking ROC and furtherly inhibiting ryanodine or caffeine sensitive calcium release, partly open ATP-Sensitive potassium channel.
IV Reasearch on vasodilative effect and mechanism of hydroxyl safflor yellow A in thoracic aorta of rats
Objective The aim was to study hydroxyl safflor yellow A(10-6M～10-1M) in isolated rat thoracic aortic ring vasodilative effect and its mechanisms. Method Isometric tension was recorded in response to drugs in organ bath. Effects of hydroxyl safflor yellow A on the vascular tone of resting, high KCl(60mmol/L) and PE(1μmol/L) pre-constricted rat thoracic aorta with or without endothelium were determined. To explore the mechanism, nitric oxide synthase inhibitor L-NAME and cyclooxygenase inhibitor indomethacin were ued. In some experiments, Effects of hydroxyl safflor yellow A(10-6M～10-1M) on the vascular tone of PE(1μmol/L)and Caf(20mol/L) pre-constricted rat thoracic aorta in Ca2+-free K-H solution were also determined. To explore the further mechanism on K+channels, ATP-Sensitive potassium channel inhibitor Gli(10μmol/L), inward rectifier potassium channel BaCl2(lmmol/L), calcium activated potassium channel TEA(1Ommol/L), voltage dependent potassium channel4-AP(1mmol/L) were also used. Result No vasomotor response to accumulated hydroxyl safflor yellow A were recorded in both resting and KCl-depolarized rings. Hydroxyl safflor yellow A(10-6M～10-1M) caused concentration relaxation of aorta rings preconstricted with PE(1μmol/L) in endothelium-intact rings. Removal of the endothelium, or pretreated with Indo could partly inhibite the relaxation of hydroxyl safflor yellow A(10-6M～10-1M). Pretreatment with L-NAME(10μmol/L) could not abolish the relaxation response to hydroxyl safflor yellow A(10-6M～10-1M). In Ca2+-free K-H solution, hydroxyl safflor yellow A(106M～10-1M) could relax PE-constricted rat thoracic aorta.4-AP could partly abolish the relaxation response to hydroxyl safflor yellow A(10-6M～10-1M). Conclusion In conclusion, hydroxyl safflor yellow A(106M～10-1M) relaxed rat aorta rings through blocking ROC, VOC and furtherly inhibiting IP3sensitive calcium release, partly open voltage dependent potassium channel. The endothelium-dependent vessel dilation of hydroxyl safflor yellow A(10-6M～10-1M) was attributed mainly to the endothelium-dependent cyclooxygenase pathway.
Conclusion GXII is multi-target therapy in cardioprotective effect, and FTA was proved to be the pharmacodynamics substance basis. FAT was similar to GXII in increasing MBF. The combination mechanisms of FTA is the GX II vasodilative mechanism. GXII relaxed thoracic aorta of rats through blocking calcium influx and intracellular calcium release extracellularly, inhibiting Ca2+release in IP3, ryanodine or Caffeine sensitive calcium pool intracellularly and mediating by opening of ATP-dependent potassium channels and voltage dependent potassium channel. The endothelium-dependent vessel dilation of GXII was attributed mainly to the endothelium-dependent NO-sGC-cGMP and cyclooxygenase pathway.
引文
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