氯沙坦对卒中易感型自发性高血压大鼠的脑保护作用

目的 研究氯沙坦对卒中易感型自发性高血压大鼠(SHRsp)脑保护作用的机制。方法 6周龄雄性SHRsp随机分为生理盐水组、小剂量氯沙坦组(10mg·kg-1·d-1)和大剂量氯沙坦组(30mg·kg-1·d-1),记录血压和脑卒中临床表现评分,18周后处死,光镜观察脑卒中的发生率和脑血管结构;电镜观察脑组织的超微结构;TUNEL法检测神经细胞凋亡。结果 大剂量氯沙坦组血压明显低于未用药组(PO.05)。对照组SHRsp死亡率、脑动脉中膜厚度/管腔半径的比值和神经细胞凋亡率均高于小剂量和大剂量氯沙坦组,差异均有显著性意义(P相似文献   

SHR大鼠脑出血急性期氨氯地平血压干预和血肿周围水肿的相关性研究

目的采用自发性高血压大鼠(SHR)脑出血模型,研究脑出血后急性期血压和血肿周围水肿的相关性。方法胶原酶法制备SHR大鼠脑出血模型,出血部位为右侧基底节区。动物随机分为脑出血组、脑出血常规剂量氨氯地平降压组、脑出血强化剂量氨氯地平降压组。MRI检查并计算血肿周围水肿大小;免疫组化及荧光定量PCR法检测血肿周围水肿的AQP4表达。结果 (1)氨氯地平治疗组MRI检测值显示,脑血肿周围水肿减轻,降压组均优于未干预组,强化降压组优于常规降压组,差异有统计学意义,第3、5、7天的F值分别为16.987、35.448、37.174(P<0.05);收缩压降低幅度和血肿周围水肿体积之间有相关性,在第3、5、7天的相关系数r分别为0.83、0.89、0.83,P=0.000;舒张压降低幅度和血肿周围水肿体积之间有相关性,在第3、5、7天的相关系数r分别为0.82、0.89、0.84,P=0.000)。(2)降压组血肿周围水肿的AQP4表达下调均优于未干预组,强化降压组优于常规降压组,差异有统计学意义,第3、5、7天的F值分别为217.058、21、51.706(P<0.05)。结论 (1)氨氯地平有效降压能使脑出血血肿周围水肿缩小;(2)氨氯地平可能通过抑制AQP4表达促使血肿周围脑水肿减轻;(3)收缩压、舒张压的升高均可促使血肿周围脑水肿扩大。     

Influence of antihypertensive treatment with budralazine on autoregulation of cerebral blood flow in spontaneously hypertensive rats

We studied the effect of chronic antihypertensive treatment with budralazine on the lower blood pressure limit of cerebral blood flow autoregulation using spontaneously hypertensive rats. Cerebral blood flow in the parietal cortex and caudate nucleus was measured to determine the lower limit using the hydrogen clearance method. The lower limit in both cerebral regions was significantly higher in 10 untreated spontaneously hypertensive rats than in 10 Wistar-Kyoto rats. The upward-shifted lower limit was restored to close to normal in the caudate nucleus and was partially restored in the parietal cortex of nine rats by 9 weeks of treatment with the high dose (50-68 mg/kg/day) of budralazine, which kept blood pressure constant at approximately normotension during the treatment period; the lower limit was slightly restored in both cerebral regions of seven rats by 4 weeks of treatment with the high dose. However, 9 weeks of treatment with the low dose (19-27 mg/kg/day) of budralazine, which produced moderate continuous hypotension in nine rats, did not apparently influence the lower limit. Our results suggest that long-term antihypertensive therapy with budralazine reduces the upward-shifted lower blood pressure limit of cerebral blood flow autoregulation toward normal and that the restoration induced by budralazine depends on the degree of blood pressure reduction as well as on the duration of the therapeutic period.     

The effect of long-term antihypertensive treatment on medial hypertrophy of cerebral arteries in spontaneously hypertensive rats

The effects of antihypertensive treatment on the structural changes of middle cerebral arteries (MCA) were studied quantitatively and morphometrically in young spontaneously hypertensive rats (SHR). Fifteen male SHR, 10 weeks of age, were divided into control and experimental groups. In the experimental group, the animals were administered hydralazine and guanethidine for the following 10 weeks. At the age of 20 weeks, mean arterial blood pressure of experimental animals was 177 +/- 9 mm Hg (mean +/- SD), being significantly lower than that of 195 +/- 12 mm Hg in control ones. Media thickness of large (external diameter greater than or equal to 200 micron) and medium sized MCA (150-200 micron) in treated SHR was 12.3 +/- 2.8 and 6.3 +/- 1.1 micron, respectively, being significantly smaller than that of 14.0 +/- 2.2 and 8.5 +/- 2.6 micron, respectively, in control SHR. The media cross-sectional area and the ratio of media thickness to external diameter were also significantly reduced by antihypertensive treatment. In the smaller vessels (75-150 micron), however, vascular morphometry revealed no difference between the two groups. Long-term antihypertensive treatment during the early phase of hypertension attenuates the development of medial hypertrophy in large cerebral arteries.     

缺血性脑卒中急性期降压治疗对预后的影响

目的 探讨降压治疗对急性缺血性脑卒中预后的影响,比较早期降压与晚期降压的差异.方法 纳入2018-10—2020-08包头医学院第一附属医院神经内科急性脑梗死合并血压升高的患者54例,随机分为早期降压组和晚期降压组,记录2组患者14 d、30 d NIHSS评分和30 d、90 d mRS评分,比较2组预后.结果 早期...     

Brain hemorrhages after rt-PA treatment of embolic stroke in spontaneously hypertensive rats.

Intracerebral hemorrhage is a major complicating factor of thrombolytic therapy of stroke. To investigate the incidence of bleeding in animals with a diseased vascular system, thrombolysis was carried out in spontaneously hypertensive rats (SHR) after clot embolism of the right middle cerebral artery (MCA). Three hours after embolism SHR were treated with either recombinant tissue-plasminogen activator (rt-PA) or saline, and neurological deficits and intracerebral hemorrhages were evaluated after 3 days survival. Rt-PA-treated SHR exhibited a significantly higher incidence of hemorrhages than untreated rats but neurological deficits and survival rates showed a non-significant trend for improvement. This model offers the possibility of investigating the pathophysiology of post-thrombolytic complications in a clinically relevant small animal model.     

Thromboxane A2 in severe hypertension and stroke in stroke-prone spontaneously hypertensive rats

Thromboxane A2 is a prostanoid having potent platelet aggregatory and vasoconstrictor properties. To determine a possible role for thromboxane A2 in the development of severe hypertension and stroke, we chronically administered the selective thromboxane A2 synthase inhibitor UK-38,485 (Dazmegrel) to stroke-prone spontaneously hypertensive rats (SHRSP). Serum thromboxane B2 (the stable hydrolysis product of thromboxane A2) generation was significantly greater in incubates of whole blood from SHRSP than in those from normotensive control Wistar-Kyoto rats and was inhibited greater than 89% by UK-38,485 administered in vivo. In 10 male SHRSP fed a Japanese-style rat chow and given 1% NaCl in drinking water to accelerate the occurrence of stroke, treatment with 100 mg/kg/day UK-38,485 by gavage starting at 8.6 weeks of age diminished systolic blood pressure elevation at 10 (205 +/- 2 vs. 220 +/- 4 mm Hg, p less than 0.01) and 11 weeks of age (210 +/- 4 vs. 239 +/- 7 mm Hg, p less than 0.01) compared with 10 untreated SHRSP. The ultimate establishment of severe hypertension was not prevented by UK-38,485. Stroke-related mortality was 70% in both UK-38,485-treated and control SHRSP at 14 weeks of age. Histologic examination revealed cerebrovascular lesions consistent with the occurrence of stroke in both control and UK-38,485-treated SHRSP. Our results support a possible role for thromboxane A2 in the elevation of blood pressure in SHRSP but do not support a possible role for the prevention of stroke by thromboxane A2 synthase inhibition in these rats.     

Lipopolysaccharide pre-treatment induces resistance against subsequent focal cerebral ischemic damage in spontaneously hypertensive rats

Ischemic tolerance was induced in spontaneously hypertensive rats (SHR) by injection of a single dose of lipopolysaccharide (LPS) (0.9 mg/kg, i.v.) 1–7 days prior to permanent middle cerebral artery occlusion (MCAO). Infarct volume, evaluated 24 h after MCAO, was significantly reduced by LPS administration 2, 3 or 4 days prior to MCAO (22.8, 25.9 and 20.5%, respectively). The beneficial effect of LPS pre-treatment was completely nullified by concurrent administration of TNFbp. On this basis, the tolerance to ischemia induced by LPS is likely to be mediated by TNF-α.     

The CBF threshold and dynamics for focal cerebral infarction in spontaneously hypertensive rats.

Two strategies were used to estimate the blood flow threshold for focal cerebral infarction in spontaneously hypertensive rats (SHRs) subjected to permanent middle cerebral artery and common carotid artery occlusion (MCA/CCAO). The first compared the volume of cortical infarction (24 h after ischemia onset) to the volumes of ischemic cortex (image analysis of [14C]iodoantipyrine CBF autoradiographs) perfused below CBF values less than 50 (VIC50) and less than 25 ml 100 g-1 min-1 (VIC25) at serial intervals during the first 3 h of ischemia. The infarct process becomes irreversible within 3 h in this model. In the second, measurements of CBF at the border separating normal from infarcted cortex at 24 h after ischemia onset were used as an index of the threshold. During the first 3 h of ischemia, VIC50 increased slightly to reach a maximum size at 3 h that closely matched the 24 h infarct volume. VIC25, in contrast, consistently underestimated the infarct volume by a factor of 2-3. CBF at the 24 h infarct border averaged 50 ml 100 g-1 min -1. Taken together, the results indicate that the CBF threshold for infarction in SHRs approaches 50 ml 100 g-1 min-1 when ischemia persists for greater than or equal to 3 h. This threshold value is approximately three times higher than in primates. Since cortical neuronal density is also threefold greater in rats than in primates, the higher injury threshold in the rat may reflect a neuronal primacy in determining the brain's susceptibility to partial ischemia.     

The nitroxide antioxidant tempol is cerebroprotective against focal cerebral ischemia in spontaneously hypertensive rats

Free radicals appear to participate in the final common pathway of neuronal death in ischemia and may therefore be an adequate target for therapy. Tempol is a nitroxide antioxidant with proven protective efficacy in several animal models, including myocardial ischemia, that has not been previously tested in models of permanent cerebral ischemia. Spontaneously hypertensive rats underwent permanent middle cerebral artery occlusion (PMCAO). Following dose-response and time-window-finding experiments rats were given vehicle or tempol (50 mg/kg) subcutaneously 1 h after PMCAO (n = 10/group). Five animals in each group were evaluated with a motor scale 24 h after the infarct and were then sacrificed and the injury volume was measured. The remaining animals were examined daily with the motor scale and also with a Morris water maze test on days 26-30 after PMCAO and sacrificed on day 30. Motor scores at all time points examined were significantly better in the tempol-treated animals (P < 0.05 for all). Significantly better performance in the water maze test for performance on days 26-30 was noted in the tempol group compared with the vehicle-treated group (P < 0.05). Injury volumes at days 1 and 30 were significantly reduced in the tempol group (9.83 +/- 1.05 vs 19.94 +/- 1.43% hemispheric volume, P = 0.0009, and 13.2 +/- 2.97 vs 24.4 +/- 2.38% hemispheric volume, P = 0.02, respectively). In conclusion, treatment with tempol led to significant motor and behavioral improvement and reduced injured tissue volumes both in the short and in the long term after stroke.     

Characterization of transient focal ischemia-induced increases in extracellular glutamate and aspartate in spontaneously hypertensive rats

Using middle cerebral artery occlusion (MCAO) and in vivo microdialysis, we have evaluated the changes in extracellular concentrations of the excitatory amino acids (EAA) glutamate and aspartate during varying periods of MCAO (0, 30, 60 min) in the striatum of spontaneously hypertensive rats (SHR). A positive correlation between occlusion time-dependent elevations in EAAs and the resulting ischemic injury was observed. This is the first demonstration of the temporal profile of EAA efflux during transient focal ischemia in SHRs. Possible sources and mechanisms of ischemia-induced EAA efflux were examined during 60 min of MCAO. Removal of Ca(2+) from the microdialysis infusion media significantly attenuated ischemia-induced increases in both glutamate (from ischemic peak of 4892 +/- 1298 to 1144 +/- 666% of preischemic values) and aspartate (from 2703 +/- 682 to 2090 +/- 599% of preischemic values). Similarly, infusion of the voltage dependent Na(+) channel blocker tetrodotoxin (TTX; 10 microM) significantly attenuated MCAO-induced increases in glutamate (to 1313 +/- 648%) and aspartate (to 359 +/- 114%). Infusion of the GLT-1 selective nontransportable inhibitor, dihydrokainate (DHK; 1 mM) also significantly attenuated the ischemia-induced increases in both EAAs (1285 +/- 508 and 1366 +/- 741% of the preischemic levels, respectively). These results indicate that during transient focal ischemia the increase in extracellular EAAs originates from both the neuronal pool, via conventional exocytotic release, and glial sources via the reversal of the GLT-1 transporter.     

Effects of long-term antihypertensive treatment on brain metabolism after bilateral carotid artery occlusion in spontaneously hypertensive rats.

The effects of antihypertensive treatment on brain metabolism after bilateral carotid occlusion were studied in spontaneously hypertensive rats. The results indicate that an increase in metabolites of ischaemic brain such as lactate and the lactate/pyruvate ratio after carotid occlusion in spontaneously hypertensive rats is apparently suppressed by treating hypertension. This suggests that hypertension may play an important role in susceptibility to cerebral ischaemia.     

Changes in ambulation and drinking behavior related to stroke in stroke-prone spontaneously hypertensive rats

In order to elucidate the behavioral changes related to stroke, ambulatory activity and water drinking were observed in stroke-prone spontaneously hypertensive rats (SHRSP). Age matched male SHRSP and Wistar Kyoto rats (WKY) were subjected to a 12 hour light and dark alternation cycle. Ambulation and drinking activity counts were determined simultaneously with an Ambulo-Drinkometer. Before stroke, ambulation and drinking activity counts in the dark phase (82%) were higher than those in the light phase (18%). Both parameters were well synchronized with the light and dark alternation cycle. With aging, daily ambulation decreased while daily drinking activity increased in SHRSP and WKY. Daily ambulation and drinking activity in 15 and 30 week old SHRSP were greater than those of WKY. It was demonstrated with an Ambulo-Drinkometer that SHRSP undergo specific behavioral changes before the onset of stroke. For instance, the 40-60 week old SHRSP showed significant individual variation in both ambulation and drinking activity. This desynchronization with the light and dark alternation cycle was followed by stroke. Twenty seven autopsies showed 11 cerebral infarctions, 10 cerebral hemorrhage and 6 cerebral hemorrhage with infarctions to be the causes of death.     

Morphological changes in spontaneously hypertensive rats

Summary Our previous studies of angiotension-induced acute hypertension showed increased intracerebral arteriolar permeability associated with markedly enhanced pinocytosis. This study was performed to determine whether similar findings occurred in spontaneous non-pharmacologically induced chronic hypertension.Cerebrovascular permeability to horseradish peroxidase (HRP) was studied over an 82-week period in spontaneously hypertensive rats (SHR) derived from a strain that originated from Japan. In a few animals increased cerebrovascular permeability to HRP was observed, associated with enhanced pinocytosis. Quantitatively, the number of pinocytotic vesicles in permeable arteriolar segments was significantly increased suggesting that enhanced pinocytosis is the principal mechanism of early cerebrovascular changes in SHR.Light microscopy of renal, ocular and cerebral vessels revealed medial hyperplasia affecting renal vessels at 16 weeks and occurring later in ocular and cerebral vessels. Deposition of fibrin in renal vessels was observed from 64 weeks onwards but was not associated with renal failure.This work was supported by the Medical Research Council of Canada, Grant No. MT 1647     

Hemorrhagic stroke development in spontaneously hypertensive rats fed a North American, Japanese-style diet

The purpose of my study was to assess a North American, Japanese-style diet commercially available from Zeigler Brothers (Gardners, Pennsylvania) with respect to the initiation of stroke development in 34 stroke-prone spontaneously hypertensive rats (spSHR) and in 14 stroke-resistant spontaneously hypertensive rats (srSHR). Nineteen spSHR fed the diet containing 4% NaCl and 0.75% K+ (low-K+ diet) from weaning had an accelerated rate of stroke development (mean +/- SEM age at death 15.3 +/- 0.5 weeks). The same diet containing 2.11% K+ (high-K+ diet) increased the mean lifespan of 15 spSHR by 39% but did not prevent stroke. The locations of hemorrhagic lesions were similar in the groups of spSHR fed high- and low-K+ diets, being nearly equally divided between the territories of the anterior, posterior, and middle cerebral arteries. The 14 srSHR fed the low-K+ diet exhibited 50% mortality at 66 weeks of age. However, in the srSHR fed the low-K+ diet, death did not result from hemorrhagic stroke. The differing incidence of stroke between the spSHR fed high- and low-K+ diets and between spSHR and srSHR fed the low-K+ diet could not be explained on the basis of differing blood pressures. Compared with spSHR fed the low-K+ diet, both srSHR fed the low-K+ diet and spSHR fed the high-K+ diet exhibited higher drinking and urine excretion rates and elevated plasma K+ levels. My study indicates the availability of a commercial North American diet that produces a predictable high incidence of stroke within a compressed time period in spSHR but not in srSHR. This diet would be useful in studies attempting to determine the events preceding and leading to the development of stroke and in determining the genetic factors responsible for stroke resistance.     

Analysis of cerebrovascular sympathetic nerve density in relation to stroke development in spontaneously hypertensive rats

Previous studies have shown that elevating the K+ levels from 0.75% to 2.11% in the diet of stroke-prone spontaneously hypertensive rats significantly retards the development of stroke and increases their lifespan. On the other hand, stroke-resistant spontaneously hypertensive rats fail to develop stroke even if they are fed the low-K+ version of this diet. Since sympathetic nerves surrounding the cerebral vasculature play an important role in protecting the brain from stroke during hypertension, I studied whether changes in sympathetic nerve density accounted for the differing incidences of stroke in stroke-prone spontaneously hypertensive rats fed high- and low-K+ diets and in stroke-resistant and stroke-prone spontaneously hypertensive rats fed a low-K+ diet. At 14 weeks of age, all 11 stroke-prone rats fed the low-K+ diet had evidence of cerebral hemorrhage while such lesions were virtually absent in the 11 littermates fed the high-K+ diet and totally absent in the eight stroke-resistant rats fed the low-K+ diet. Stroke-prone (regardless of diet) but not stroke-resistant rats exhibited greater sympathetic nerve densities in the left hemisphere than in the right. When stroke-prone rats were compared, in some areas of the cerebrovasculature, rats fed the high-K+ diet had greater mean sympathetic nerve densities than those fed the low-K+ diet. On the other hand, stroke-resistant and stroke-prone rats fed the low-K+ diet exhibited comparable sympathetic nerve densities in most cerebral arteries studied.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of allopurinol on ischemia and reperfusion-induced cerebral injury in spontaneously hypertensive rats

In spontaneously hypertensive rats, we studied the participation of xanthine oxidase-linked free radical in ischemia and reperfusion-induced cerebral injury, using allopurinol, a xanthine oxidase inhibitor. The loss of righting reflex was noted in some animals after a 4 hour occlusion of bilateral common carotid arteries and 19 of 25 animals died within 72 hours after reperfusion. One hour after reperfusion, the cerebral water content increased significantly, with an increase in sodium content and a decrease in potassium content. In 7 animals treated with oral administrations of allopurinol (200 mg/kg) 24 hours and 1 hour before occlusion, no death was found either during occlusion or after reperfusion, and the loss of righting reflex was noted in only one animal 24-72 hours following reperfusion. The increase in cerebral water content and accompanied changes in electrolyte contents were clearly prevented by allopurinol. These results suggest the possibility that the production of xanthine oxidase-linked free radical participates in cerebral injury due to ischemia and reperfusion in spontaneously hypertensive rats.     

Beta-adrenoceptor-mediated vascular relaxation in spontaneously hypertensive rats

Although the impairment of beta-adrenoceptor (beta-AR)-induced vascular relaxation to isoprenaline has been extensively described, discrepancy persisted in the literature. In this work, we investigated beta-AR-induced relaxation in spontaneously hypertensive and normotensive rats aorta. We attempted to determine beta-AR subtypes involved in order to understand the conflicting data regarding the beta-AR-induced vasodilation to isoprenaline. Aortic rings isolated from 12-week-old Wistar Kyoto (WKY) rats and spontaneously hypertensive rats (SHRs) were placed in organ baths and constricted with phenylephrine (alpha1-AR agonist). Then, cumulative concentration-relaxation curves (CCRC) to AR agonists were constructed. In intact aortic rings from both strains, isoprenaline (a nonselective beta-AR agonist) (0.001-10 microM) induced similar concentration-dependent relaxations. CCRC was shifted to the right and upward in the presence of nadolol (a nonspecific beta1 and beta2-AR antagonist) (10 microM). After endothelium removal, the response to isoprenaline was partly inhibited in WKY rats, but was strongly inhibited in SHRs. In WKY rats, isoprenaline-induced endothelium-independent relaxation was not modified in the presence of nadolol but was inhibited in the presence of CGP 20712A (low-affinity-state beta1-AR antagonist). In endothelium-denuded rings, SR 58611A (a preferential beta3-AR agonist) (0.1-30 microM) produced a very small relaxation in both strains. In WKY rats, CGP 12177 (CGP) (0.1-30 microM) and cyanopindolol (0.01-3 microM) (partial beta3-AR and low-affinity-state beta1-AR agonists with beta1-AR and beta2-AR antagonistic properties) produced endothelium-independent relaxations. CGP-induced effect was significantly inhibited by CGP 20712A (10 microM) or bupranolol (10 microM) (low-affinity-state beta1-AR antagonists). In SHRs, similarly to the impaired endothelium-independent relaxation to isoprenaline, endothelium-independent relaxations to CGP and cyanopindolol were greatly blunted. These relaxations were not modified in the presence of CGP 20712A. In endothelium-denuded rings pretreated with pertussis toxin, CGP-induced relaxation was not modified in WKY rats, but was partly restored in SHRs. In conclusion, these results showed, that in 12-week-old SHRs, the endothelium-independent component of the relaxation to isoprenaline was impaired, and this impairment could involve the low-affinity-state beta1-AR. G(i) protein overexpression and/or overstimulation may be possible factors that contribute to this alteration in hypertension.