Mortality and cerebral metabolism after bilateral carotid artery ligation in normotensive and spontaneously hypertensive rats.

Mortality and cerebral glycolytic metabolism were studied after bilateral ligation of the common carotid artery in normotensive Wistar rats (NTR), and spontaneously hypertensive rats (SHR) derived from Wistar strain. In the first 24 hours after occlusion of carotid arteries, 72 per cent of 108 SHR died, whereas it was fatal in only 16 per cent of 43 NTR. In SHR, cerebral lactate and cerebral lactate/pyruvate ratio (L/P ratio) increased by 12.4 and 12.1 times the control, respectively at five to six hours after ligation, and remained raised even in rats surviving for two to three days thereafter. Changes in cerebral lactate and L/P ratio were minimal in NTR. Cerebral ATP decreased markedly at five to six hours after ligation in SHR studied. These results indicate that bilateral carotid artery ligation causes severe brain damage in SHR but not in NTR, suggesting hypertension per se to be operative for the development of cerebral ischaemia.     

CEREBRAL LACTATE, PYRUVATE and ATP CONCENTRATIONS, and ARTERIAL ACID-BASE BALANCE AT VARIOUS TIME INTERVALS FOLLOWING BILATERAL CAROTID ARTERY OCCLUSION IN NORMOTENSIVE and SPONTANEOUSLY HYPERTENSIVE RATS

Cerebral lactate, pyruvate and adenosine triphosphate (ATP), and arterial acid-base balance were measured in normotensive rats (NTR) and spontaneously hypertensive rats (SHR) at various time intervals following bilateral carotid occlusion. In SHR, a great and progressive increase in cerebral lactate and lactate/pyruvate ratio (L/P ratio) during the first 5–6 hours after occlusion was followed by a gradual decrease as the time interval increased. Cerebral ATP in SHR decreased as cerebral lactate increased, and an inverse relationship was observed between lactate and ATP. On the other hand, in NTR, there were minimal changes in cerebral lactate and L/P ratio following carotid occlusion. These results suggest that bilateral carotid occlusion might cause severe ischemic damages of the brain in SHR, but not in NTR. the hemodynamic factor as a cause of cerebral ischemia in hypertensives is discussed.     

Platelet emboli in rat brain cross when the contralateral carotid artery is occluded

The pathogenesis of embolic events ipsilateral to an occluded carotid artery is uncertain. To examine this question we combined occlusion of the left common carotid artery with embolism from the right common carotid artery in rats. Following ligation of the left carotid artery in 20 experimental rats, we irradiated the right carotid artery with a laser (632 nm, 200 mW/cm2, 12-15 minutes) following the intravenous injection of 12.5 mg/kg of the photosensitizing agent Photofrin II. Controls had left carotid artery occlusion with (n = 13) or without (n = 6) Photofrin II. Fifteen of the 20 experimental rats survived to be perfused at 24 hours; cerebral infarcts were identified in 12 rats, with bilateral infarcts in 10. There were 112 infarcts (101 small [less than 2.5 mm] and 11 large [greater than 2.5 mm] on the right and 103 (93 small and 10 large) on the left. Emboli were seen in association with some infarcts and were evenly distributed in the two hemispheres (37 emboli on the right and 40 on the left, with the midline azygous artery occluded in four animals). Left carotid artery occlusion did not produce infarcts or emboli in the controls. We conclude that cerebral infarcts in the distribution of an occluded common carotid artery may be caused by emboli from the contralateral carotid artery in rats.     

Normalization of endothelial and inducible nitric oxide synthase expression in brain microvessels of spontaneously hypertensive rats by angiotensin II AT1 receptor inhibition.

Inhibition of angiotensin II AT1 receptors protects against stroke, reducing the cerebral blood flow decrease in the periphery of the ischemic lesion. To clarify the mechanism, spontaneously hypertensive rats (SHR) and normotensive control Wistar Kyoto (WKY) rats were pretreated with the AT1 receptor antagonist candesartan (0.3 mg. kg.(-1) d(-1)) for 28 days, a treatment identical to that which protected SHR from brain ischemia, and the authors studied middle cerebral artery (MCA) and common carotid morphology, endothelial nitric oxide synthase (eNOS) and inducible nitric oxide synthase (iNOS) messenger RNA (mRNA), and protein expression in cerebral microvessels, principal arteries of the Willis polygon, and common carotid artery. The MCA and common carotid artery of SHR exhibited inward eutrophic remodeling, with decreased lumen diameter and increased media thickness when compared with WKY rats. In addition, there was decreased eNOS and increased iNOS protein and mRNA in common carotid artery, circle of Willis, and brain microvessels of SHR when compared with WKY rats. Both remodeling and alterations in eNOS and iNOS expression in SHR were completely reversed by long-term AT1 receptor inhibition. The hemodynamic, morphologic, and biochemical alterations in hypertension associated with increased vulnerability to brain ischemia are fully reversed by AT1 receptor blockade, indicating that AT1 receptor activation is crucial for the maintenance of the pathologic alterations in cerebrovascular circulation during hypertension, and that their blockade may be of therapeutic advantage.     

Oedema-related tissue damage after temporary and permanent occlusion of the middle cerebral artery

Oedema-related tissue damage after temporary and permanent occlusion of the middle cerebral arteryEleven adult spontaneously–hypertensive male rats (SHR) were studied 2 2 h or 7 days after a 2 h unilateral occlusion of the right middle cerebral artery (MCA). Another 11 SHR were studied after 24 h or 7 days of permanent MCA ligation. The brain infarcts were significantly larger ( P < 0.05) after permanent occlusion than after a 2h occlusion. More extensive and widespread vasogenic oedema, emanating from the infarcts, was visualized immunohistochemically in the temporarily–ligated animals and the relative number of astrocytes in their contralateral hemispheres was greater, thereby indicating that the vasogenic oedema influences the degree of gliosis. An immunopositivity for albumin but not for fibrinogen extended via the white matter into the ipsilateral thalamic nuclei, where cytolytic nerve cell damage, severely shrunken and karyorrhectic nerve cells as well as gliosis were found one week after permanent and temporary MCA ligation. The histological changes in the thalamus indicated a difference in timing between lateral and medial parts of the lesion as well as between temporarily–and permanently–ligated SHR. These findings together with the close spatial correlation with albumin immunoreactivity indicate that the spread of extravasated plasma constituents or degradation products with the oedema bulk flow from the infarct influences the timing, character and extent of thalamic lesions after cerebral infarction.     

Brain edema after middle cerebral artery occlusion

The right middle cerebral artery (MCA) was occluded either during 30 min or permanently, in normotensive Wistar Kyoto (WKY) and spontaneously hypertensive (SHR) rats. The rats were killed 2, 6 or 24 h later. Brain specific gravity, an indicator of brain edema, was determined on samples from the prefrontal, frontal, parietal and occipital cortex and the caudate nucleus. In SHR the brain specific gravity was significantly reduced in the right hemisphere at 2, but not at 6 or 24 h after a temporary occlusion. After permanent ligation, the specific gravity markedly decreased with time in the right hemisphere in SHR with significant difference from WKY, as well as from the left hemisphere, at all intervals. Our data support the concept that chronic hypertension aggravates ischemic brain edema after an arterial ligation.     

Different susceptibilities to cerebral infarction in spontaneously hypertensive (SHR) and normotensive Sprague-Dawley rats

Rapid occlusion of the middle cerebral artery (MCA) was undertaken in 5-6 week old rats to determine whether or not the young spontaneously hypertensive rat (SHR) or the normotensive Sprague-Dawley rat (SD) is protected against cerebral infarction by collateral circulation. Rats were killed 3 days after MCA occlusion and administration of Evans blue. As compared to SD, the SHR had elevated blood pressure prior to MCA occlusion, large cortical infarcts marked with Evans blue, and motor deficits contralateral to the occluded MCA. SHR did not develop an adequate collateral circulation, but SD were protected from infarction by it. Because the cerebral lesions were in young spontaneously hypertensive rats living prior to the established form of hypertension, the increased susceptibility to infarction was not secondary to it. Since normotensive rats usually do not infarct after sudden MCA occlusion, the infarction trait may be linked to the mechanism causing elevated blood pressure in spontaneously hypertensive rats.     

Cerebral air embolism and the blood-brain barrier in the rat

Cerebral air embolism can have hemodynamic effects such as increases in blood pressure and cerebral blood flow. It has been suggested that these factors play a role for the induction of the blood-brain barrier (BBB) dysfunction. In the present study, 5 microliters air was injected into the right internal carotid artery from a catheter in the external carotid artery after ligation of the extracerebral branches. No consistent change in blood pressure was observed with this small amount of air. Hypercapnia, which increases protein leakage in the brain under conditions of high intraluminal pressure, significantly reduced the extravasation in air embolism. Lidocaine and SITS (4 acetamido-4-isothiocyano-stilbene-2,2-disulfonic acid disodium), two drugs that effectively reduce the albumin leakage in acute hypertension, had no prophylactic effect in cerebral air embolism. Spontaneously hypertensive rats are less vulnerable than normotensive rats to pressure-induced BBB dysfunction but did not significantly differ from controls regarding albumin leakage in the present study. It is concluded that the increased cerebrovascular permeability in air embolism is not related to hemodynamic factors.     

Effects of hyperventilation on cerebral blood flow and brain tissue metabolism in normotensive and spontaneously hypertensive rats

Cerebral vascular carbon dioxide (CO2) reactivities were compared in normotensive (NTR) and hypertensive (SHR) rats. Cerebral blood flow (CBF) in cortex and thalamus were evaluated before and during one hour of hyperventilation. After one hour of hyperventilation brain lactate, pyruvate, and ATP concentrations were also determined. Significant and similar reductions of CBF due to hyperventilation induce hypocapnia were found in both NTR and SHR groups. In contrast the percent increase in cerebrovascular resistance (CVR) per unit decrease in paCO2 was significant, indicating that hypocapnia induced vasoconstriction is greater in NTR than in SHR groups. During hyperventilation the average value for lactate in the NTR group was 3.98 mM/kg. In contrast it was 3.15 mM/kg in the SHR group, a significant difference (p less than 0.05). When paCO2 fell below 15 mm Hg the cerebral lactate increased strikingly in the NTR group and cortical CVR was reduced suggesting that an accumulation of the ischemic metabolites caused dilatation of the constricted cerebral vessels. In contrast the SHR group disclosed no such changes. The increase CVR characteristic of SHR appeared to diminish the cerebral vasoconstrictive response to hypocapnia. As a result ischemic metabolites in the brain do not increase in this group to the degree that they do in NTR.     

Small deep cerebral infarcts associated with occlusive internal carotid artery disease. A hemodynamic phenomenon?

Small deep cerebral infarcts, often referred to as lacunes, have been traditionally associated with small-vessel disease affecting the deep penetrating arterial system. We describe 10 cases where these infarcts were associated with severe, ipsilateral internal carotid artery occlusive disease. Seven of these patients also had severe occlusive disease of the contralateral internal carotid artery. The clinical and radiologic features, in combination with studies of cerebral blood flow, were consistent with hemodynamically mediated cerebral ischemia. Occlusive internal carotid artery disease may be more commonly associated with hemodynamic cerebral ischemia than previously believed, and small cerebral infarcts in the deep arterial border zone areas are likely to be an important manifestation of this process.     

Effects of aging and hypertension on endothelium-dependent vascular relaxation in rat carotid artery

We evaluated the effects of aging and hypertension on endothelium-dependent relaxation of rat common carotid arteries using 14-week-old (young) and 11-month-old (old) Wistar-Kyoto rats (WKY) and age-matched spontaneously hypertensive rats (SHR). Isometric tension of common carotid artery ring segments was measured. With a resting tension of 2.0 g determined from the baseline tension-contraction curves, precontraction was induced by 10(-5) M 5-hydroxytryptamine and endothelium-dependent relaxation was measured by application of either acetylcholine or adenosine 5'-triphosphate (ATP). Mean arterial blood pressure was 73.1 +/- 3.0 mm Hg in WKY and 110.0 +/- 3.1 mm Hg in SHR. These baseline values were significantly different. Acetylcholine-induced maximal relaxations were 70.1 +/- 2.6% of the 5-hydroxytryptamine-induced contraction in young WKY, 45.6 +/- 2.1% in old WKY, 35.1 +/- 1.8% in young SHR, and 21.4 +/- 2.5% in old SHR. On the other hand, ATP-induced relaxations were 52.0 +/- 3.2%, 35.7 +/- 3.8%, 21.7 +/- 3.5%, and 17.0 +/- 1.8% in the groups, respectively. Acetylcholine-induced relaxations were significantly different between WKY and SHR, young and old, independently. On the other hand, ATP-induced relaxations were also significantly different between young and old WKY, although no significant difference was observed between young and old SHR. The fact that endothelium-dependent relaxation of a cephalic artery is impaired in old rats and in hypertensive rats suggests that aging and hypertension are risk factors that may augment the disturbance of the cerebral circulation in pathologic conditions.     

Arterial sympathetic innervation and cerebrovascular diseases in original rat models

The role of the arterial sympathetic innervation in cerebrovascular pathology was investigated in new experimental models using Brown Norway (BN) and Long-Evans (LE) rats. The BN rat is susceptible to intracerebral hemorrhage (ICH) within the cerebral cortex when rendered hypertensive whereas the LE rat is prone to cerebral aneurysms (CAs) in arteries of the circle of Willis with hypertension and carotid ligation. Noradrenaline (NA) content, determined by high performance liquid chromatography (HPLC), was lower both in the caudal and cerebral arteries in the BN than in the LE rat. Denervation of cerebral arteries by superior cervical ganglionectomy did not increase ICH lesion incidence in BN hypertensive rats. A possible link between the level of caudal artery NA content and the occurrence of ICH lesions and CAs was studied in rats from two distinct BNXLE crosses: back-cross (BC) rats (F1XBN) and F2 rats (F1XF1) which respectively display, with hypertension and carotid ligation, a high incidence of either ICH lesions or CAs. In BC rats, the level of caudal artery NA content was not related to ICH lesion occurrence. However, in F2 rats a low caudal artery NA content was associated with a high incidence of ruptured CAs. Thus, a low arterial sympathetic innervation may participate in mechanisms leading to rupture of CAs.     

Mechanisms and clinical features of posterior border-zone infarcts

BACKGROUND: Previous studies link posterior border-zone cerebral infarcts between the middle cerebral artery (MCA) and the posterior cerebral artery (PCA) to hemodynamic causes, not embolism. OBJECTIVE: To study the cause of these infarcts. METHODS: We studied 21 patients (unilateral = 18, bilateral = 3) with acute, symptomatic posterior border-zone infarcts shown on CT or MRI to clarify stroke mechanisms. Patients were identified by review of CT and MRI logs and medical records during a 35-month period. An embolic mechanism was assigned when a source of embolism from either the heart, aorta, or parent large artery was present in the absence of intrinsic MCA or PCA disease. A hemodynamic mechanism was assigned when systemic hypotension was present. RESULTS: Among patients with unilateral lesions, 10 were embolic (7 cardiac, 3 carotid), 7 were unknown, and one patient had vasospasm from a ruptured aneurysm. Visual field abnormalities predominated over motor, sensory, and language abnormalities. All patients with bilateral posterior border-zone lesions had perioperative hypotension. Prolonged lethargy, bilateral limb weakness, and cortical blindness were common. CONCLUSIONS: Embolism, either cardiac or from the parent carotid artery, is the predominant stroke mechanism in unilateral posterior border-zone infarcts, not distal field perfusion failure. Bilateral posterior border-zone infarcts have a distinctive clinical presentation and are caused by systemic hypotension. Variability of irrigation of the major arteries, passage of emboli to border-zone areas, and decreased clearance of emboli in these areas explain the findings in the patients with unilateral lesions.     

Involvement of internal elastic lamina in development of induced cerebral aneurysms in rats

To elucidate the role of the internal elastic lamina in the development of cerebral aneurysm, the bifurcation of the anterior cerebral artery and olfactory artery was histologically studied in control and experimental rats treated with unilateral carotid ligation and renal hypertension. Various stages of aneurysm formation were compared, and it was found that early aneurysmal changes were always present just distal to the apical intimal pad on the anterior cerebral artery side. The internal elastic lamina was thinned and fragmented just distal to the pad even in the very early stage of aneurysm formation when the medial layer was still present. In control rats, the internal elastic lamina had a tendency to thin and fragment at the site where aneurysms would develop in experimental rats. Our study shows that changes of the internal elastic lamina were present just distal to the pad even in control rats, which never develop cerebral aneurysms. Under hemodynamic stress augmented by experimental treatments, further degenerative changes of the internal elastic lamina and involvement of the medial layer are considered to occur and result in aneurysm formation there.     

单侧颈内动脉狭窄或闭塞的影像学梗死类型及脑血流动力学评价

目的研究单侧动脉粥样硬化性颈内动脉狭窄或闭塞(ICASO)性脑梗死患者影像学梗死类型及其脑血流动力学改变,以探讨脑梗死发生的可能机制。方法 87例经脑血管造影明确诊断的单侧动脉粥样硬化性ICASO性脑梗死患者,MRI和TCD检查分析影像学梗死类型及不同类型之间存在的脑血流动力学差异。结果 MRI所见脑梗死类型共分为区域梗死(30例,34.48%)、皮质下梗死(27例,31.03%)、边缘带梗死(18例,20.69%)和弥散小梗死(12例,13.79%),不同脑梗死类型发生率之间差异具有统计学意义(χ~2=7.156,P=0.028);脑梗死类型与颈内动脉狭窄程度呈负相关(r=-0.275,P=0.010),重度狭窄以皮质下梗死、边缘带梗死多见(均11/36,30.56%),完全闭塞则以区域梗死常见(17/34,50.00%)。脑血流动力学观察显示,不同脑梗死类型患侧大脑中动脉平均血流速度和搏动指数与健侧存在明显的不对称性(均P=0.000),其中以区域梗死最低,次之为边缘带梗死。结论 ICASO以区域梗死多见,且脑血流动力学障碍存在于各种脑梗死类型中。提示应综合考虑脑梗死类型和脑血流动力学改变,从而选择恰当的防治方法。     

Pinealectomy aggravates and melatonin administration attenuates brain damage in focal ischemia.

Large infarcts develop in pinealectomized rats subjected to middle cerebral artery occlusion, which was attributed to loss of antioxidant action of melatonin. However, melatonin also has vascular actions, and pinealectomy may induce hypertension. The authors investigated (1) whether hemodynamic factors contribute to infarct development in pinealectomized rats, (2) whether melatonin administration can reverse the unfavorable effect of pinealectomy on infarct formation, and (3) whether melatonin can reduce the infarct volume in nonpinealectomized rats subjected to focal transient ischemia (2 hours middle cerebral artery occlusion, 22 hours reperfusion). Rats were pinealectomized 3 months before ischemia to eliminate any possible action of pinealectomy-induced hypertension on stroke. Blood pressure and regional CBF values during ischemia and reperfusion were not significantly different between pinealectomized and sham-operated rats, suggesting that pinealectomy-induced increase in infarct was not related to hemodynamic factors. The infarct volume resumed to the level of sham-operated rats on melatonin administration. Injection of melatonin (4 mg/kg) before both ischemia and reperfusion reduced infarct volume by 40% and significantly improved neurologic deficit scores in pinealectomized as well as sham-operated rats subjected to middle cerebral artery occlusion. These data suggest that physiologic melatonin release as well as exogenously given melatonin has a neuroprotective action in focal cerebral ischemia.     

Clinical and hemodynamic aspects of low-flow infarcts

We used single-photon emission computed tomography to measure cerebral blood flow, cerebral blood volume, and cerebral perfusion reserve and transcranial Doppler sonography with CO2 stimulation to assess hemispheric vasomotor reactivity in 37 patients and in normal controls. Computed tomography and magnetic resonance imaging were performed to differentiate morphologically low-flow infarcts (n = 17) from territorial infarcts (n = 20). In patients with either type of infarct, blood flow was decreased and blood volume was increased in the infarcted areas compared with the same areas in the controls. Perfusion reserve and vasomotor reactivity were significantly reduced in patients with territorial infarcts and carotid artery occlusions (n = 12) and even more reduced in patients with low-flow infarcts (p less than 0.001). Both parameters were normal in patients with cardiac embolic territorial infarcts (n = 8). In patients with territorial infarcts, blood flow and perfusion reserve changes were restricted to the infarcted areas, whereas in patients with low-flow infarcts, regions of decreased perfusion reserve considerably exceeded the area of the infarct. Low-flow infarcts are related to the hemodynamic effects of severe extracranial carotid artery disease.     

Cerebral infarction due to carotid occlusion and carbon monoxide exposure. II. Influence of preganglionic cervical sympathectomy.

Unilateral cerebral infarcts were produced in the rat by ligation of one common carotid artery and subsequent exposure to carbon monoxide. The incidence and extension of brain infarcts was increased in animals with additional ipsilateral cervical preganglionic sympathectomy. Sympathectomy did not affect markedly the respiration and systemic circulation. The effect of sympathectomy was attributed to a cutaneous vasodilation, leading to an extracranial steal phenomenon.     

单侧颈动脉闭塞脑梗死和侧支代偿情况分析

目的 通过计算机断层扫描（computer tomography,CT）和磁共振成像（magnetic resonance imaging,MRI）研究闭塞颈动脉同侧半球的梗死情况,分析不同侧支的代偿能力,增进我们对梗死机制的理解。方法 颈部血管彩色超声证实的43例单侧颈动脉闭塞患者,将颈动脉闭塞同侧的大脑半球分为大脑中动脉皮层区域、前皮层分水岭区域、后皮层分水岭区域、内分水岭区域、穿支动脉供血区域,比较各个解剖区域发生梗死情况,并分析侧支代偿种类和不同解剖部位梗死的关系。结果 颈动脉闭塞时,内分水岭区发生梗死最多见19例（44.2%）,8例前皮层分水岭梗死有6例伴有内分水岭区梗死。后交通动脉（posterior communicating artery,PCoA）出现是减少内分水岭区梗死的保护性因素[比值比（odd ratio,OR）为0.226,95%可信区间（confidence interval,CI）在0.058～0.833间,P =0.027]。结论 颈动脉闭塞时,内分水岭区发生梗死最多见,提示内分水岭区是对血流下降最敏感的区域。PCoA开放能够减少内分水岭区梗死。     

Experimental cerebral ischemia after bilateral common carotid artery ligation in SHRSP, SHRSR and Wistar rats: correlation between blood pressure and degree of ischemia

Three different pressure groups of rats, stroke-prone spontaneously hypertensive rats (SHRSP, 200-270 mmHg), stroke-resistant SHR (SHRSR, 160-240 mmHg), and Wistar rats (WR, 120-160 mmHg) were used to investigate the effect of prior existing hypertension on the severity of brain damage induced by ischemia. The cerebral ischemia was induced by bilateral common carotid artery ligation (BLCL) and the survival rate, cerebral blood flow, cerebral energy metabolites (ATP, lactate c-AMP) and water content were measured. Colloidal carbon perfusion was also performed. Sixteen-week-old male rats were used. The survival rate was observed until 24 hours after BLCL. Cerebral blood flow was measured in parietal cortex by hydrogen clearance method. ATP was measured by luciferin-luciferase method, and lactate by enzymatic method using LDH. c-AMP was measured by radioimmunoassay. Brain water content was measured by freeze-dry method. These measurements were done for animals surviving 6 hours of BLCL. Colloidal carbon perfusion was done according to Ames' Method. The survival rate was lower in the hypertension group. The survival of SHRSP and SHRSR were 20% compared to 71% in WR after 24 hours of BLCL. The cerebral circulation of SHRSP fell abruptly and was near to zero after one hour of BLCL. In SHRSR this fall of cerebral blood flow was prominent in the rats of higher blood pressure. On the other hand there was no apparent fall of cerebral blood flow in WR after BLCL. The cerebral energy metabolites. ATP and c-AMP showed the lowest level in SHRSP which had the negative correlation to blood pressure.(ABSTRACT TRUNCATED AT 250 WORDS)