脑卒中防治新策略的初步探索
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摘要
高血压病发生率高，在中国成人高血压病的发生率高达18％，目前我国有1.6亿高血压患者。脑卒中是高血压病最重要的并发症之一，中国高血压病人脑卒中的发生率要远远高于欧美国家的高血压病人。脑卒中一旦发生，后果严重，病人非死即残。全球每年新发脑卒中1500万，其中500万人死亡，500万人永久性残废。要使幸存者恢复功能，耗时费力。因此，就脑卒中而言，防止其发生比治疗更重要。如何预防脑卒中的发生?已知血压水平是一个非常重要的危险因素和预测因子，美国预防、检测、评估与治疗高血压全国联合委员会第七次报告(JNC-7)指出血压与心血管事件危险的关系是连续的、一致的，且独立于其它危险因素；血压越高，发生心肌梗死、心力衰竭、脑卒中和肾病的危险就越大。在临床中，抗高血压治疗平均可以降低35-40％的脑卒中发生。
从上述情况可以看到，控制血压对预防心血管事件具有重要的意义。但是临床试验表明，单一用药一般仅可控制40％～60％甚至更少患者的血压，对重度高血压的控制效果更差。JNC-7和2003年欧洲高血压协会—欧洲心脏病学协会关于动脉高血压治疗指南均明确指出为了达到目标血压，大部分患者需要用一种以上的抗高血压药物进行联合治疗。但是关于联合用药预防脑卒中的研究，鲜有报道。我们以前的研究工作证实氨氯地平和阿替洛尔具有良好的协同作用，本项目工作的第一部分是观察氨氯地平和阿替洛尔的组方对脑卒中的预防作用。
但是除血压水平以外，脑卒中的发生肯定还存在其他影响因素，我们有必要对脑卒中的病理生理机制进行深入的研究，找出血压以外的其他决定因子或者预防措施，以便将来针对这些因子或措施进行干预，作为预防脑卒中的新策略。动脉压力感受性反射(arterial baroreflex，ABR)功能，是心血管系统活动最重要的自身调节机制之一，ABR功能强弱可以用压力感受性反射敏感性(baroreflex sensitivity，BRS)这一指标来表示。近年来研究发现，ABR功能的异常，参与了多种心血管系统疾病的发生发展过程。研究也发现在脑卒中动物模型以及慢性脑血管疾病的病人BRS受损。Robinson等发现，脑卒中发生后，病人BRS功能低下者，其生存预后较BRS正常者明显要差。这些均提示ABR功能与脑卒中之间存在密切的联系。因此，我们假设BRS是一个独立于其他影响因素，如血压水平，影响脑卒中发生重要的因素，BRS决定急性脑卒中发生的损害程度。所以实验的第二部分研究了BRS在急性脑梗死发生中作用。
因此本课题拟研究：
(1)阿替洛尔与氨氯地平合用对SHR-SP脑卒中发生的预防作用；
(2)动脉压力感受性反射功能与急性脑梗死关系。
第一部分阿替洛尔与氨氯地平合用对SHR-SP脑卒中发生的预防作用
应用脑卒中倾向的自发性高血压大鼠(SHR-SP)证实氨氯地平和阿替洛尔预防脑卒中的作用，包括2个实验。
实验一、急性实验：氨氯地平和阿替洛尔联合用药对SHR-SP血流动力学的影响。24只雌性SHR-SP，8月龄，随机分为3组，每组8只，测定基础血压及BRS，然后分别胃内给予：阿替洛尔10mg／kg，或氨氯地平1mg／kg，或阿替洛尔+氨氯地平10+1mg／kg。再次测定血压及BRS。结果显示：单独及联合给药均能显著降低SHR-SP血压水平，联合用药效果更加显著；稳定血压方面，单用对于血压的波动性没有显著的影响，联合用药可以显著的稳定血压；单用以及联合用药均对BRS没有显著的影响；经Q值检验，证实联合用药具有协同作用。
实验二、长期实验：氨氯地平和阿替洛尔联合用药对SHR-SP脑卒中发生的预防作用。选用5月龄SHR-SP，80只，雌雄各半，随机分为4组，即对照组及3个药物治疗组。治疗组分别给予阿替洛尔10mg／kg／d，或氨氯地平1.0mg／kg／d，或阿替洛尔+氨氯地平10+1.0mg／kg／d。长期给药，观察脑卒中死亡情况。结果显示三个药物均能显著延长SHR-SP大鼠的寿命，联合用药效果更为显著。
第二部分动脉压力感受性反射功能与急性脑梗死关系
利用2种不同的ABR功能缺陷实验模型，验证ABR功能是否影响急性脑梗死程度，包括2个实验。
实验一、10周龄雄性Sprague-Dawley(SD)大鼠，进行去窦弓神经(SAD)手术，破坏反射功能，一个月后，进行大脑中动脉栓塞术(MCAO)，观察脑梗死情况，并测定炎症因子的浓度。对照组(n=10)采用假手术，不破坏反射功能。结果显示SAD组(n=8)脑梗死程度明显较假手术组严重，血清中IL-6等炎症因子释放增加。
实验二、10周龄雄性SD大鼠，孤束核内注射SP-SAP致ABR功能破坏，2周后再进行MCAO，观察脑梗死情况。对照组(n=6)孤束核内注射人工脑脊液。实验结果与实验一类似，即孤束核内注射SP-SAP破坏反射功能组(n=6)大鼠急性脑梗死损伤较对照组严重。
结论：阿替洛尔和氨氯地平10+1mg／kg／d联合用药，对SHR-SP具有良好的协同降压作用，长期给药可以显著的延缓脑卒中发生的时问，延长SHR-SP大鼠寿命；ABR功能是影响急性脑梗死损害程度的重要指标之一。
Hypertension is a disease with a high prevalence, in China the morbility ofhypertension reached 18 percent and nowadays the hypertensive population is about160 millions. The hypertensive complications are often lethal, especially the stroke. Ithas been reported that the rate of stroke among the hypertensive patients in China isfar higher than the western countries. According to recent estimates published by theWorld Health Organization, about 15 million people per year fall victim to strokeworldwide, of who 5 million die and another 5 million are left permanently disabled.Many stroke survivors become dependent, and require lifelong assistance. Therefore,prevention is the only possible way to curb the stroke pandemic. Blood pressure levelis one of the most consistent and powerful predictor of stroke, so blood pressurecontrol is an important way to reduce the morbidity of stroke. A recent surveyorganized by United Committee of American for Hypertension Therapy andPrevention indicated that blood pressure is an independent factor that has highcorrelation with cardiovascular incidence. The higher the blood pressure is, the higherincidence of myocardial infarct, heart failure, stroke and renal lesion will happen. Inclinical antihypertensive therapy prevent stroke incidence 35 to 40 percent.
Notably, it is important to control blood pressure control for stroke prevention.Clinical trial showed combination therapy against hypertension using 2 or more drugsfrom different classes produce better drug efficacy than the use of single drug, whichwas considered only to control 40 to 60 percents of hypertensive patients.Furthermore, the use of such synergistic therapy is also recommended for the initialtreatment of hypertension. Therefore the European Hypertension and HeartAssociation pointed out that for most of the hypertensive patients 2 or more kinds ofantihypertensive drugs are needed for blood pressure control. However, up to nowlittle has been reported about the effects of combination use of drugs on stroke. Ourprevious studies has demonstrated that combination use of atenolol and amlodipine had synergistic effects on lowering and stabilizing blood pressure in hypertensive rats.One of the purpose of this study was designed to investigate the influence ofcombination use of atenolol and amlodipine on prevention of stroke in stroke-pronespontaneously hepertensive rats.
However, blood pressure level is not the unique determinant for stroke. Besideblood pressure, other important determinants for stroke are available. It is necessary toexplore the physiological and pathophysiological mechanism about the developmentof stroke. Arterial baroreflex function is one of the most important mechanisms in theregulation of cardiovascular activities. Since the end of 1980s, the pathologicalimportance of Arterial baroreflex function has attracted the attention of manyinvestigators. Baroreflex function, expressed as baroreflex sensitivity, was found as animportant determinant of cardiac death aider acute myocardial infarction. There is alsoestablished evidence of abnormal baroreflex sensitivity in animal models of stroke andpatients with chronic cerebrovascular disease. Indeed, it was found that baroreflexsensitivity was impaired after acute stroke. Post-stroke patients with impairedbaroreflex sensitivity had a poor prognosis. These suggested that close correlationcould exist between stroke and arterial baroreflex function. Therefore we hypothesizethat baroreflex sensitivity is one of independent factor, which could affect thedevelopment of stroke and its severity. The second part of this study was to evaluatethe action of baroreflex sensitivity on acute cerebral infarct size induced by middlecerebral arterial occlusion.
In this study we focused on the following two issues, that is:
1. Combination use of atenolol and amlodipine on prevention of stroke instroke-prone spontaneously hepertensive rats;
2. Action ofbaroreflex sensitivity on acute cerebral infarct size induced by middlecerebral arterial occlusion.
Part One: Combination use of atenolol and amlodipine on prevention of stroke instroke-prone spontaneously hepertensive rats
In this part two experiments were designed.
Experiment one: Effects of combination use of atenolol and amlodipine on bloodpressure and baroreflex sensitivity in stroke-prone spontaneously hepertensive rats. 24animals, aged 8 months, were randomly divided into 3 groups. Baseline values ofblood pressure and baroreflex sensitivity were determined, and then the 3 groupsintragastrically received atenolo 10.0 mg/kg, or amlodipine 1.0 mg/kg, or atenolol andamlodipine 10.0+1.0 mg/kg respectively, blood pressure and baroreflex sensitivitywere determined again. Compared with the baseline values, it was found that eithersingle or combination use of the drugs significantly reduced blood pressure, andcombination use produced a more profound blood pressure decrease; Combination usealso significantly decreased blood pressure variability, neither atenolol nor amlodipineused alone had this effect; Either atenolol, or amlodipine, or combination use of themdid not changed the baroreflex sensitivity level. Probability sum test (Q value test)demonstrated that combination use had synergistic effects on both blood pressurereduction and its stabilization.
Experiment two: Combination use of atenolol and amlodipine on prevention ofstroke. 80 stroke-prone spontaneously hepertensive rats, aged 5 months, wererandomly divided into 4 groups. One group served as control, the other 3 groups weretreated with atenolo 10.0 mg/kg/d, or amlodipine 1.0 mg/kg/d, or atenolol andamlodipine 10.0+1.0 mg/kg/d respectively. All of them were carefully observedeveryday, the survive time were recorded. Compared with the control group, thelifespan of the three treated ones was significantly prolonged. However, the lifespanof the combination group was the longest.
Part two: Action of baroreflex sensitivity on acute cerebral infarct size induced bymiddle cerebral arterial occlusion
In this part, two experimental arterial baroreflex function deficiency model wereused to investigate the influence of baroreflex sensitivity on acute cerebral infarct sizeinduced by middle cerebral arterial occlusion.
Experiment one: Male SD rats, aged 10 weeks, were used for sinoaorticdenervation or sham operation. One month later both the sinoaortic denervated group(n=8) and the sham one (n=10) were subjected to middle cerebral arterial occlusion.24h after operation, rats were sacrificed by exsanguinations. The cerebral infarct size,and plasma TNFαand IL-6 were determined. It was found the infarct size of thesinoaortic denervated group was increased when compared with the sham one, and theplasma TNFαand IL-6 concentration were significantly increased in sinoaorticdenervated group.
Experiment two: Male SD rats, aged 10 weeks, were used for nucleus solitariusinjection of SP-SAP or aCSF. Two weeks later both (n=6 in each group) receivedmiddle cerebral arterial occlusion and the cerebral infarct size were comparedbetween the two groups. Compared with the control group, the SP-SAP treated onesuffered a more serious cerebral infarct.
Conclusion: Combination use of atenolol and amlodipine (10.0+1.0 mg／kg/d)possessed synergistic effects on both reducing and stabilizing blood pressure, longterm administration of them significantly delayed the stroke occurrence and prolongedthe lifespan in stroke-prone spontaneously hepertensive rats; Damaged arterialbaroreflex function aggravated the severity of cerebral infarct size induced by middlecerebral arterial occlusion in SD rats.
从上述情况可以看到，控制血压对预防心血管事件具有重要的意义。但是临床试验表明，单一用药一般仅可控制40％～60％甚至更少患者的血压，对重度高血压的控制效果更差。JNC-7和2003年欧洲高血压协会—欧洲心脏病学协会关于动脉高血压治疗指南均明确指出为了达到目标血压，大部分患者需要用一种以上的抗高血压药物进行联合治疗。但是关于联合用药预防脑卒中的研究，鲜有报道。我们以前的研究工作证实氨氯地平和阿替洛尔具有良好的协同作用，本项目工作的第一部分是观察氨氯地平和阿替洛尔的组方对脑卒中的预防作用。
但是除血压水平以外，脑卒中的发生肯定还存在其他影响因素，我们有必要对脑卒中的病理生理机制进行深入的研究，找出血压以外的其他决定因子或者预防措施，以便将来针对这些因子或措施进行干预，作为预防脑卒中的新策略。动脉压力感受性反射(arterial baroreflex，ABR)功能，是心血管系统活动最重要的自身调节机制之一，ABR功能强弱可以用压力感受性反射敏感性(baroreflex sensitivity，BRS)这一指标来表示。近年来研究发现，ABR功能的异常，参与了多种心血管系统疾病的发生发展过程。研究也发现在脑卒中动物模型以及慢性脑血管疾病的病人BRS受损。Robinson等发现，脑卒中发生后，病人BRS功能低下者，其生存预后较BRS正常者明显要差。这些均提示ABR功能与脑卒中之间存在密切的联系。因此，我们假设BRS是一个独立于其他影响因素，如血压水平，影响脑卒中发生重要的因素，BRS决定急性脑卒中发生的损害程度。所以实验的第二部分研究了BRS在急性脑梗死发生中作用。
因此本课题拟研究：
(1)阿替洛尔与氨氯地平合用对SHR-SP脑卒中发生的预防作用；
(2)动脉压力感受性反射功能与急性脑梗死关系。
第一部分阿替洛尔与氨氯地平合用对SHR-SP脑卒中发生的预防作用
应用脑卒中倾向的自发性高血压大鼠(SHR-SP)证实氨氯地平和阿替洛尔预防脑卒中的作用，包括2个实验。
实验一、急性实验：氨氯地平和阿替洛尔联合用药对SHR-SP血流动力学的影响。24只雌性SHR-SP，8月龄，随机分为3组，每组8只，测定基础血压及BRS，然后分别胃内给予：阿替洛尔10mg／kg，或氨氯地平1mg／kg，或阿替洛尔+氨氯地平10+1mg／kg。再次测定血压及BRS。结果显示：单独及联合给药均能显著降低SHR-SP血压水平，联合用药效果更加显著；稳定血压方面，单用对于血压的波动性没有显著的影响，联合用药可以显著的稳定血压；单用以及联合用药均对BRS没有显著的影响；经Q值检验，证实联合用药具有协同作用。
实验二、长期实验：氨氯地平和阿替洛尔联合用药对SHR-SP脑卒中发生的预防作用。选用5月龄SHR-SP，80只，雌雄各半，随机分为4组，即对照组及3个药物治疗组。治疗组分别给予阿替洛尔10mg／kg／d，或氨氯地平1.0mg／kg／d，或阿替洛尔+氨氯地平10+1.0mg／kg／d。长期给药，观察脑卒中死亡情况。结果显示三个药物均能显著延长SHR-SP大鼠的寿命，联合用药效果更为显著。
第二部分动脉压力感受性反射功能与急性脑梗死关系
利用2种不同的ABR功能缺陷实验模型，验证ABR功能是否影响急性脑梗死程度，包括2个实验。
实验一、10周龄雄性Sprague-Dawley(SD)大鼠，进行去窦弓神经(SAD)手术，破坏反射功能，一个月后，进行大脑中动脉栓塞术(MCAO)，观察脑梗死情况，并测定炎症因子的浓度。对照组(n=10)采用假手术，不破坏反射功能。结果显示SAD组(n=8)脑梗死程度明显较假手术组严重，血清中IL-6等炎症因子释放增加。
实验二、10周龄雄性SD大鼠，孤束核内注射SP-SAP致ABR功能破坏，2周后再进行MCAO，观察脑梗死情况。对照组(n=6)孤束核内注射人工脑脊液。实验结果与实验一类似，即孤束核内注射SP-SAP破坏反射功能组(n=6)大鼠急性脑梗死损伤较对照组严重。
结论：阿替洛尔和氨氯地平10+1mg／kg／d联合用药，对SHR-SP具有良好的协同降压作用，长期给药可以显著的延缓脑卒中发生的时问，延长SHR-SP大鼠寿命；ABR功能是影响急性脑梗死损害程度的重要指标之一。
Hypertension is a disease with a high prevalence, in China the morbility ofhypertension reached 18 percent and nowadays the hypertensive population is about160 millions. The hypertensive complications are often lethal, especially the stroke. Ithas been reported that the rate of stroke among the hypertensive patients in China isfar higher than the western countries. According to recent estimates published by theWorld Health Organization, about 15 million people per year fall victim to strokeworldwide, of who 5 million die and another 5 million are left permanently disabled.Many stroke survivors become dependent, and require lifelong assistance. Therefore,prevention is the only possible way to curb the stroke pandemic. Blood pressure levelis one of the most consistent and powerful predictor of stroke, so blood pressurecontrol is an important way to reduce the morbidity of stroke. A recent surveyorganized by United Committee of American for Hypertension Therapy andPrevention indicated that blood pressure is an independent factor that has highcorrelation with cardiovascular incidence. The higher the blood pressure is, the higherincidence of myocardial infarct, heart failure, stroke and renal lesion will happen. Inclinical antihypertensive therapy prevent stroke incidence 35 to 40 percent.
Notably, it is important to control blood pressure control for stroke prevention.Clinical trial showed combination therapy against hypertension using 2 or more drugsfrom different classes produce better drug efficacy than the use of single drug, whichwas considered only to control 40 to 60 percents of hypertensive patients.Furthermore, the use of such synergistic therapy is also recommended for the initialtreatment of hypertension. Therefore the European Hypertension and HeartAssociation pointed out that for most of the hypertensive patients 2 or more kinds ofantihypertensive drugs are needed for blood pressure control. However, up to nowlittle has been reported about the effects of combination use of drugs on stroke. Ourprevious studies has demonstrated that combination use of atenolol and amlodipine had synergistic effects on lowering and stabilizing blood pressure in hypertensive rats.One of the purpose of this study was designed to investigate the influence ofcombination use of atenolol and amlodipine on prevention of stroke in stroke-pronespontaneously hepertensive rats.
However, blood pressure level is not the unique determinant for stroke. Besideblood pressure, other important determinants for stroke are available. It is necessary toexplore the physiological and pathophysiological mechanism about the developmentof stroke. Arterial baroreflex function is one of the most important mechanisms in theregulation of cardiovascular activities. Since the end of 1980s, the pathologicalimportance of Arterial baroreflex function has attracted the attention of manyinvestigators. Baroreflex function, expressed as baroreflex sensitivity, was found as animportant determinant of cardiac death aider acute myocardial infarction. There is alsoestablished evidence of abnormal baroreflex sensitivity in animal models of stroke andpatients with chronic cerebrovascular disease. Indeed, it was found that baroreflexsensitivity was impaired after acute stroke. Post-stroke patients with impairedbaroreflex sensitivity had a poor prognosis. These suggested that close correlationcould exist between stroke and arterial baroreflex function. Therefore we hypothesizethat baroreflex sensitivity is one of independent factor, which could affect thedevelopment of stroke and its severity. The second part of this study was to evaluatethe action of baroreflex sensitivity on acute cerebral infarct size induced by middlecerebral arterial occlusion.
In this study we focused on the following two issues, that is:
1. Combination use of atenolol and amlodipine on prevention of stroke instroke-prone spontaneously hepertensive rats;
2. Action ofbaroreflex sensitivity on acute cerebral infarct size induced by middlecerebral arterial occlusion.
Part One: Combination use of atenolol and amlodipine on prevention of stroke instroke-prone spontaneously hepertensive rats
In this part two experiments were designed.
Experiment one: Effects of combination use of atenolol and amlodipine on bloodpressure and baroreflex sensitivity in stroke-prone spontaneously hepertensive rats. 24animals, aged 8 months, were randomly divided into 3 groups. Baseline values ofblood pressure and baroreflex sensitivity were determined, and then the 3 groupsintragastrically received atenolo 10.0 mg/kg, or amlodipine 1.0 mg/kg, or atenolol andamlodipine 10.0+1.0 mg/kg respectively, blood pressure and baroreflex sensitivitywere determined again. Compared with the baseline values, it was found that eithersingle or combination use of the drugs significantly reduced blood pressure, andcombination use produced a more profound blood pressure decrease; Combination usealso significantly decreased blood pressure variability, neither atenolol nor amlodipineused alone had this effect; Either atenolol, or amlodipine, or combination use of themdid not changed the baroreflex sensitivity level. Probability sum test (Q value test)demonstrated that combination use had synergistic effects on both blood pressurereduction and its stabilization.
Experiment two: Combination use of atenolol and amlodipine on prevention ofstroke. 80 stroke-prone spontaneously hepertensive rats, aged 5 months, wererandomly divided into 4 groups. One group served as control, the other 3 groups weretreated with atenolo 10.0 mg/kg/d, or amlodipine 1.0 mg/kg/d, or atenolol andamlodipine 10.0+1.0 mg/kg/d respectively. All of them were carefully observedeveryday, the survive time were recorded. Compared with the control group, thelifespan of the three treated ones was significantly prolonged. However, the lifespanof the combination group was the longest.
Part two: Action of baroreflex sensitivity on acute cerebral infarct size induced bymiddle cerebral arterial occlusion
In this part, two experimental arterial baroreflex function deficiency model wereused to investigate the influence of baroreflex sensitivity on acute cerebral infarct sizeinduced by middle cerebral arterial occlusion.
Experiment one: Male SD rats, aged 10 weeks, were used for sinoaorticdenervation or sham operation. One month later both the sinoaortic denervated group(n=8) and the sham one (n=10) were subjected to middle cerebral arterial occlusion.24h after operation, rats were sacrificed by exsanguinations. The cerebral infarct size,and plasma TNFαand IL-6 were determined. It was found the infarct size of thesinoaortic denervated group was increased when compared with the sham one, and theplasma TNFαand IL-6 concentration were significantly increased in sinoaorticdenervated group.
Experiment two: Male SD rats, aged 10 weeks, were used for nucleus solitariusinjection of SP-SAP or aCSF. Two weeks later both (n=6 in each group) receivedmiddle cerebral arterial occlusion and the cerebral infarct size were comparedbetween the two groups. Compared with the control group, the SP-SAP treated onesuffered a more serious cerebral infarct.
Conclusion: Combination use of atenolol and amlodipine (10.0+1.0 mg／kg/d)possessed synergistic effects on both reducing and stabilizing blood pressure, longterm administration of them significantly delayed the stroke occurrence and prolongedthe lifespan in stroke-prone spontaneously hepertensive rats; Damaged arterialbaroreflex function aggravated the severity of cerebral infarct size induced by middlecerebral arterial occlusion in SD rats.
引文
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