Study On The Prevention And Treament Of Stroke In Rats

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 ratsIn 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 occlusionIn 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.