Cerebral vasoconstrictor responses to serotonin after dietary treatment of atherosclerosis: implications for transient ischemic attacks

Serotonin, which is released when platelets aggregate at carotid lesions, may contribute to cerebral ischemia. Our goal was to test the hypothesis that dietary treatment of atherosclerosis reverses the augmented cerebral vasoconstrictor response to serotonin. We studied normal cynomolgus monkeys, atherosclerotic monkeys, and atherosclerotic monkeys that were fed a normal (regression) diet for 18 months. Morphometric studies indicated that the regression diet reduced intimal area in the carotid arteries by about 50-75%. Cerebral blood flow was measured with microspheres, and microvascular pressure was measured with a micropipette in pial arteries that were approximately 300 micron in diameter. Values for cerebral blood flow and arteriolar pressure were used to calculate resistance of large cerebral arteries (greater than 300 micron diameter). Infusion of serotonin produced a modest increase in the resistance of large cerebral arteries in normal monkeys. Vasoconstrictor responses to serotonin were increased more than fivefold in atherosclerotic monkeys. The major finding of the study is that dietary treatment of atherosclerosis abolishes augmented cerebral responses to serotonin.     

Effects of atherosclerosis on cerebral vessels: hemodynamic and morphometric studies

In this study hemodynamic and morphometric consequences of atherosclerosis were examined in cynomolgus monkeys. We tested the hypothesis that atherosclerosis augments cerebral vasoconstrictor responses to serotonin. We studied 8 normal and 8 atherosclerotic monkeys, which were fed an atherogenic diet for 17 months. Morphometric studies indicated marked intimal proliferation of extracranial carotid arteries, with only modest reduction in the vascular lumen, as atherosclerotic lesions were displaced outward. Cerebral blood flow was measured with microspheres and microvascular pressure was measured with a micropipette in pial arteries approximately 350 microns diameter. Intracarotid infusion of serotonin reduced microvascular pressure, which indicates constriction of large arteries upstream, but cerebral blood flow did not decrease. Serotonin produced a 2-fold greater reduction in cerebral microvascular pressure in atherosclerotic monkeys than in normal monkeys. Intracarotid histamine increased flow and hypocapnia reduced flow in both normal and atherosclerotic monkeys, without altering cerebral microvascular pressure. We conclude: First, atherosclerosis potentiates constrictor responses to serotonin in large cerebral arteries. Because platelets release serotonin when they aggregate, augmentation of responses by atherosclerosis may have implications for cerebral vascular responses during aggregation of platelets at carotid lesions. Second, despite marked proliferation of intima, atherosclerotic lesions are displaced outward during a prestenotic phase of the disease, so that the lumen is relatively well preserved.     

Effects of antihypertensive drugs on blood velocity: implications for prevention of cerebral vascular disease.

The treatment of high blood pressure prevents death from congestive heart failure, hypertensive nephropathy, and encephalopathy, and strokes from cerebral arteriolar disease (lacunes, hemorrhage from microaneurysms). However, atherosclerosis, manifested as coronary artery disease is just as frequent a cause of death in well-controlled hypertensives as in poorly-controlled patients. Increasing evidence suggests that increased blood velocity, by causing turbulence and high shear rates at the endothelial surface of arteries, may be important in the pathogenesis of atherosclerosis. Turbulence has been observed in cerebral berry aneurysms. In order to measure the effects of antihypertensive agents on blood velocity, a new method of analysing Doppler ultrasound velocity recordings has been developed. Studies in Rhesus monkeys show the following: In doses which reduce diastolic pressure by 13-28%, propranolol decreased mean blood velocity (MV) by 17%, clonidine decreased MV by 14%, while methyldopa increased MV 12%, and hydralazine increased MV by 52%. (p less than .00001). It is hypothesized that enlargement of berry aneurysms, the progression of cerebral atherosclerosis, and embolism from carotid lesions might all be decreased by the selection of antihypertensive agents which decrease blood velocity.     

中青年脑梗塞患者的临床与病理

目的 探讨中，青年人脑梗塞的病因。方法 将连续尸检确诊的脑梗塞病例中≤４５岁患者的脑标本常规处理，以动脉为重点行肉眼及光镜下观察，并分析有关临床资料。结果 ７２例患者中≤４５岁者７例，其中男６例，女１例，其中高血压，风湿性心脏病各２例，嗜烟，嗜酒中４例，病前１日酗酒１例。便塞灶相关动脉闭塞处管壁５例发现粥样斑块，３例发现炎症（１例与粥样斑并存）。５例粥样斑块血栓形成均位于基底动脉，４例病后２日内死     

Effect of atherosclerosis on cerebral vascular responses to activation of leukocytes and platelets in monkeys

The goal of this study was to test the hypothesis that atherosclerosis alters responses of cerebral arteries and the ocular circulation to the activation in vivo of leukocytes and platelets. We measured blood flow to the brain and eye using microspheres and pressure in the cerebral microvessels of normal and atherosclerotic monkeys. The intracarotid injection of 10(-7) M N-formyl-L-methionyl-L-leucyl-L-phenylalanine to activate leukocytes did not alter cerebral blood flow in 11 normal or 10 atherosclerotic monkeys but increased the resistance of large cerebral arteries by 46 +/- 11% (mean +/- SEM) in the atherosclerotic animals. The injection of N-formyl-L-methionyl-L-leucyl-L-phenylalanine did not alter blood flow to the eye in 10 normal monkeys but decreased blood flow to the choroid by 38 +/- 9% in 11 atherosclerotic monkeys. The intracarotid injection of 3 x 10(-9) M prostaglandin E2, a leukocyte product, produced an increase in the resistance of large cerebral arteries in five atherosclerotic but not in six normal monkeys. Prostaglandin E2 reduced blood flow to the retina and choroid in the atherosclerotic monkeys by 62 +/- 22% and 65 +/- 17%, respectively. The intracarotid infusion of 25 micrograms/min collagen to activate platelets increased cerebral blood flow by 21 +/- 5% in 10 normal monkeys but did not alter it in 11 atherosclerotic monkeys. Collagen did not alter blood flow to the choroid in 10 normal monkeys but decreased it by 29 +/- 8% in 11 atherosclerotic monkeys.(ABSTRACT TRUNCATED AT 250 WORDS)     

Atherosclerosis potentiates constrictor responses of cerebral and ocular blood vessels to thromboxane in monkeys

The goal of our study was to examine the effects of infusion of serotonin and the thromboxane A2 analogue U46619 into one carotid artery to stimulate their release from platelets during aggregation. We measured blood flow to the brain and eye using microspheres and cerebral microvascular pressure in the pial arteries of normal and atherosclerotic cynomolgus monkeys. Unilateral intracarotid infusion of 10-30 micrograms/min serotonin did not affect cerebral blood flow in normal or atherosclerotic monkeys; serotonin did not alter blood flow to the eye in normal monkeys but decreased flow to the retina and choroid in atherosclerotic monkeys by 39 +/- 11% and 44 +/- 10% (mean +/- SEM), respectively. Infusion of 30 ng/min U46619 did not alter cerebral blood flow but increased the pressure gradient from the aorta to the pial artery, which is an index of large-artery resistance, in atherosclerotic monkeys. U46619 had no effect on blood flow to the eye in normal monkeys but decreased blood flow to the retina and choroid by 71 +/- 14% and 53 +/- 13%, respectively, in atherosclerotic monkeys. Thus, atherosclerosis potentiates the constrictor responses of large cerebral arteries to thromboxane and the responses of blood vessels of the eye to thromboxane and serotonin.     

Influence of monosialoganglioside inner ester on neurologic recovery after global cerebral ischemia in monkeys

We assessed the consequences of transitory global cerebral ischemia and the influence of monosialoganglioside inner ester (AGF 2) treatment on neurologic outcome, cerebral blood flow, and cerebral metabolic rate in monkeys over 48 hours. Global cerebral ischemia was produced by a cervical tourniquet and a lowering of blood pressure to 6.65 kPa; recirculation followed after 30 minutes. AGF 2 (30 mg/kg) was administered intravenously immediately after initiation of recirculation and intramuscularly twice a day for 48 hours. Our results show that treatment with AGF 2 significantly accelerated the rate of neurologic recovery. Improvement was evident 5 hours after ischemia; full neurologic recovery was observed in half of the monkeys 48 hours after ischemia. This recovery was associated with a less severe reduction in cerebral blood flow without a concomitant increase in the cerebral metabolic rate.     

Risk factors for stroke in middle-aged men in G?teborg, Sweden

To evaluate stroke risk factors in G?teborg, Sweden, during 1970-1973 a cohort of 7,495 participating men from a general population sample of 9,998 men aged 47-55 years were examined with respect to cardiovascular risk factors. Men with hypertension and hypercholesterolemia and men who were heavy smokers were treated. We assessed stroke end points and cause-specific mortality using a stroke register and death certificates. During a mean follow-up of 11.8 years, 230 strokes occurred in the entire population sample (participants and nonparticipants) (7% subarachnoid hemorrhages, 13% intracerebral hemorrhages, 42% cerebral infarctions, and 38% unspecified strokes). Using univariate analysis, we found measured high blood pressure (systolic and diastolic), smoking, known hypertension, diabetes mellitus, stroke in either parent, severe psychological stress, marital status, atrial fibrillation, previous transient ischemic attacks, previous myocardial infarction, effort-induced chest pain, and intermittent claudication to be significantly related to all stroke. Of the stroke types, subarachnoid hemorrhage was not related to any of these indicators, and intracerebral hemorrhage was related only to measured high blood pressure. Using multivariate analyses, we found measured high blood pressure, smoking, and severe psychological stress as well as atrial fibrillation, previous transient ischemic attacks, and intermittent claudication to be independent risk factors for nonhemorrhagic stroke. Serum cholesterol concentration, occupational and leisure-time physical activity, body mass index, alcohol abuse, and low occupational class were not risk factors for stroke.     

Recurrence of embolic stroke in non-valvular atrial fibrillation (NVAF). An autopsy study

From 3434 consecutive autopsied cases over 60 years of age, we performed retrospective, clinicopathological examinations on 81 patients with symptomatic embolic stroke and non-valvular atrial fibrillation (NVAF) who had not received anticoagulant therapy during their lives. Twenty-one had recurrent embolic strokes (recurrence rate: 25.9%). In the thrombotic infarction without NVAF, the recurrence rate was 21.4%. Recurrent strokes occurred earlier in the embolic infarction of NVAF than in the thrombotic infarction. Most of the lesions of initial embolic strokes were present in the territory of one middle cerebral artery (MCA), while many lesions of recurrent strokes were found in the territory of the contralateral MCA. Between the NVAF cases with and without recurrent embolic stroke, there was no significant difference in the background condition such as history of hypertension, duration of NVAF, severity of cerebral arterial atherosclerosis, heart weight, intracardiac thrombi, myocardial infarctions and infarctions in other systemic organs.     

A PET study following treatment with a pharmacological stressor,FG7142, in conscious rhesus monkeys

FG7142 is a benzodiazepine partial inverse agonist, which is known as a pharmacological stressor. Several reports demonstrated that FG7142 produced anxiety in humans, non-human primates, and rodents, and impaired working memory in non-human primates and rodents. In this study, we examined the effect of FG7142 on cerebral blood flow and glucose metabolism using positron emission tomography (PET) in conscious rhesus monkeys. Male rhesus monkeys were intramuscularly treated with FG7142 (0.2 or 1.0 mg/kg, n=5, respectively), and regional cerebral blood flow (rCBF) and regional cerebral metabolic rate of glucose (rCMRglc) were measured by PET 20 min and 40 min after treatment, respectively. During PET measurement, physiological parameters and plasma cortisol levels were monitored. FG7142 significantly decreased rCBF in the thalamus and rCMRglc in all brain regions examined in a dose-dependent manner without changes in physiological parameters. FG7142 also significantly increased plasma cortisol levels. The present study may provide an important insight into the understanding of the pathophysiology of anxiety and stress-related disorders in humans, and strongly suggesting that prevention of anxiety or stress is important when measuring conscious brain function.     

An apparatus and behavioral training protocol to conduct positron emission tomography (PET) neuroimaging in conscious rhesus monkeys

Nonhuman primates offer a unique resource in neuroimaging research, providing the opportunity to manipulate appropriate biological and behavioral variables under well-controlled experimental conditions in an animal model that is closely related to humans, both functionally and neuroanatomically. The present report describes the development and standardization of PET neuroimaging protocols in conscious rhesus monkeys and their application to characterize the acute effects of cocaine on cerebral blood flow. Specific attention was devoted to the development of an effective and comfortable head restraint device to be used in the imaging of conscious monkeys. The restraint device was designed to attach to a standard primate chair to facilitate frequent immobilization. Subjects received extensive behavioral training prior to neuroimaging in order to ensure their comfort and minimize potential stress associated with the imaging protocols. Functional changes in cerebral blood flow were characterized in three subjects with the positron-emitting tracer 15O water following acute i.v. administration of cocaine. Regions of interest were defined on MRI scans with a high degree of accuracy. Cocaine caused pronounced increases in cerebral blood flow at 5 min postinjection that diminished markedly within 25 min. The results document the feasibility to conduct PET neuroimaging studies of cerebral blood flow in conscious nonhuman primates. Extension of the methodology to include brain activation during behavioral studies could contribute significantly to the growing discipline of behavioral neuroscience.     

脑超深低温下猴脑血流阻断时间窗的研究

目的 探明选择性脑超深低温技术对常温条件下猴脑血流阻断有效治疗时间窗.方法 10只恒河猴分为3组:常温组(n=3);深低温I组(n=4):脑血流阻断15min开始深低温治疗;深低温Ⅱ组(n=3):脑血流阻断20min开始深低温治疗.双侧颈动脉和颈静脉系统分离、脑血流阻断建立严重脑缺血缺氧模型.深低温组动物通过一侧颈内动脉灌注4~C林格氏液同侧颈内静脉回流,阻断其他颈动脉和颈静脉血管,脑温维持在(15.3±1.04)℃、中心体温(35.1±1.10)℃.维持深低温60min后恢复正常脑血流.常温组动物采用相同方法脑灌注37℃林格氏液.观察猴生存率、脑神经功能状况和病理形态.结果 4只脑血流阻断15min开始深低温治疗的猴死亡3只、1只长期存活;3只脑血流阻断20min开始深低温治疗和3只常温组猴全部死亡.死亡动物脑干出现神经元死亡.结论 常温条件下严重或完全脑缺血缺氧有效低温复苏时间为10min、15min内低温复苏成功率高,15min以上开始深低温复苏效果差.     

Concurrence of iris aneurysms and cerebral hemorrhage in hypertensive rabbits.

The development of miliary aneurysms of the iris is associated with the high risk of cerebral hemorrhage in rabbits with renal hypertension. The high-risk group of hypertensive rabbits in this series was characterized by the formation of iris aneurysms, and this group developed a striking proportion of hemorrhagic strokes (42.5%). In the low-risk group of hypertensive rabbits that did not develop aneurysms of the iris, only a low proportion of cerebral hemorrhages were found (11%). The development of iris aneurysms in rabbits was directly proportional to increments in level of blood pressure, and their rate of formation was very rapid. The formation of miliary aneurysms of the circular artery of the iris in hypertensive rabbits is likely related to the common embryologic origin and the morphologic similarity between perforating arteries of the brain and the principal arterial vessel of the iris.     

Vascular risk factors in dementia

This review describes differing profiles of vascular risk factors in different types of dementia. Although vascular risk factors are related to various types of strokes, their independent effect on the occurrence of poststroke dementia appears to be small. Various risk factors have been identified for microangiopathy-related cerebral abnormalities, such as white matter changes and lacunae, which are the core lesions for the development of a vascular dementia syndrome without stroke symptoms. Most consistently, arterial hypertension and diabetes mellitus have been found to be associated with such brain abnormalities. Diastolic blood pressure seems to be of particular importance as recent investigations demonstrate that this factor is related to the course of multiple lacunar strokes and the progression of white matter disease. Epidemiological studies report that various vascular risk factors including arterial hypertension, diabetes mellitus, and atrial fibrillation may also be associated with Alzheimer’s disease. There is also evidence of a direct relationship between Alzheimer’s disease and general atherosclerosis. Further investigations are needed to determine whether these associations are due to the weakness of diagnostic criteria, or whether vascular risk factors indeed modulate the clinical expression of primary degenerative dementia. Common susceptibility genes leading to shared risk factors may be one of the reasons for a higher coincidence of Alzheimer’s disease and vascular dementia than can be expected by chance. A modulatory effect of vascular risk factors in the development of primary degenerative dementia may extend treatment options. Received: 30 August 1999/Accepted: 1 October 1999     

Cerebral atherosclerosis in Parkinsonian patients

Cerebral atherosclerosis has been previously postulated as a possible etiology for Parkinsonism. Epidemiological studies, however, have suggested a relatively low incidence of ischemic strokes in Parkinsonian patients. The aim of this study was to evaluate the prevalence of extra- and intracranial atherosclerosis in these patients. We performed carotid duplex studies and transcranial Doppler (TCD) examinations in 50 patients with idiopathic Parkinson's disease and in 50 healthy control subjects. The carotid duplex scanning results revealed fewer Parkinsonian patients with stenotic lesions (30% versus 38% in the control group; p=0.4). The TCD results demonstrated lower peak flow velocities in the Parkinsonian group versus the control group, and these differences were statistically significant in the basilar, vertebral and right middle cerebral arteries (p=0.03, 0.001 and 0.04, respectively). The carotid duplex scanning results could not provide a potential explanation for the relatively low occurrence of stroke in Parkinsonian patients, because most strokes are related to carotid atherosclerotic lesions while the TCD results might reflect a diminished blood supply secondary to a decline in tissue metabolism.     

Treatment of Acute Ischemic Stroke: Beyond Thrombolysis and Supportive Care

The initial therapeutic approach to acute ischemic stroke consists of thrombolytic therapy and early initiation of supportive care, usually commenced prior to the determination of the underlying stroke etiology. Varying stroke mechanisms may call for specific, etiology-based treatment. The majority of strokes result from cardioembolism, large-vessel atherothromboembolism, and small-vessel occlusive disease. There are scant data to support the use of acute anticoagulation therapy over anti-platelet therapy in cardioembolic stroke and large-vessel atherosclerosis, although it may be reasonable in a certain subset of patients. However, augmentation of blood flow with early surgery, stenting, or induced hypertension, may play a role in patients with large artery stenosis. The less commonly identified stroke mechanisms may warrant special consideration in treatment. Controversy remains regarding the optimal anti-thrombotic treatment of arterial dissection. Reversible cerebral vasoconstriction syndrome may benefit from therapy with calcium channel blockers, high-dose steroids, or magnesium, although spontaneous recovery may occur. Inflammatory vasculopathies, such as isolated angiitis of the central nervous system and temporal arteritis, require prompt diagnosis as the mainstay of therapy is immunosuppression. Cerebral venous thrombosis is a rare cause of stroke, but one that needs early identification and treatment with anticoagulation. Rapid determination of stroke mechanism is essential for making these critical early treatment decisions.     

Dietary treatment of atherosclerosis abolishes hyperresponsiveness of retinal blood vessels to serotonin in monkeys.

BACKGROUND AND PURPOSE: Atherosclerosis alters vascular responses of the eye to serotonin. Augmented vasoconstrictor responses in the retina to serotonin are associated with functional impairment and may contribute to amaurosis fugax. The goal of this study was to test the hypothesis that dietary treatment of atherosclerosis restores vascular responses of the eye toward normal. METHODS: We measured blood flow to the retina using microspheres in six normal monkeys, five atherosclerotic monkeys, and five atherosclerotic monkeys that were fed a normal (regression) diet for 18 months. RESULTS: Infusion of 8 and 40 micrograms.min-1.kg-1 serotonin into the left atrium had little effect on blood flow to the retina in normal monkeys. In contrast, the high dose of serotonin reduced blood flow to the retina by a mean +/- SEM of 81 +/- 9% (p less than 0.05) in atherosclerotic monkeys. In monkeys that were fed the regression diet, serotonin had no effect on blood flow to the retina. CONCLUSIONS: Regression of atherosclerosis abolishes augmented responses of the retinal circulation to serotonin.     

Raised intracranial pressure and cerebral blood flow: I. Cisterna magna infusion in primates

Changes in cerebral blood flow during incremental increases of intracranial pressure produced by infusion of fluid into the cisterna magna were studied in anaesthetized baboons. Cerebral blood flow remained constant at intracranial pressure levels up to approximately 50 mm Hg. At intracranial pressure levels between 50-96 mm Hg a marked increase in cerebral blood flow occurred, associated with the development of systemic hypertension and changes in cerebrovascular resistance. Further increases of intracranial pressure led to a progressive fall in cerebral blood flow. Prior section of the cervical cord prevented both the increase in cerebral blood flow and the systemic hypertension. Alteration of cerebral perfusion pressure by bleeding during the hyperaemia in a further group of animals suggested that autoregulation was at least partially preserved during this phase. After maximum hyperaemia had occurred, however, autoregulation appeared to be lost. The clinical implications of these findings are discussed.     

Cerebrale Vasoparalyse,arterielle Hypertension und Hirnödem

The present studies were performed in order to determine whether "filtration edema" will develop as a consequence of cerebral vasoparalysis, vasoparalysis in combination with arterial hypertension or arterial hypertension alone. A series of dogs, anaesthetised with i.v. Chloralose-Urethane were exposed 1) to cerebral vasoparalysis, produced by hypercapnia (PaCO2 about 150 mm Hg) and hypoxaemia (PaO2 40-60 mm Hg); 2) to arterial hypertension and 3) to a combination of cerebral vasoparalysis and arterial hypertension. Following cerebral vasoparalysis and arterial hypertension, a significant decrease of total cerebrovascular resistance and moderate increase of venous resistance was observed. Regional cerebral blood flow (133Xe), intracranial pressure, as well as the pressure in postcapillary venous outflow (sinus sagittalis wedge pressure and confluence sinuum pressure) were increased. Neither normotonic vasoparalysis nor vasoparalysis in combination with slight arterial hypertension (MABP more than 90 min above 180 mm Hg) resulted in cerebral edema. In contrast, cerebral vasoparalysis in combination with severe arterial hypertension (MABP more than 90 min above 220 mm Hg) resulted in a statistically significant increase in the water content in the white matter without evidence of protein extravasation. Multiple small foci of Evans blue extravasates, however, were found in the cortex following arterial hypertension in combination with vasodilation, indicating a damage of the blood brain barrier. In these blue stained cortical areas the water content was significantly in creased. The following conclusions were drawn from the results. Vasoparalysis during normotension does not produce brain edema despite the slightly elevated hydrostatic pressure gradient between intravasal and extracellular space. Only considerable increase of this hydrostatic pressure gradient caused by a combination of vasoparalysis with severe arterial hypertension is able to produce brain edema in the white matter. In addition, acute hypertension may cause minor multifocal damage of the blood brain barrier in the cerebral cortex. It is concluded that so-called brain swelling, which has been described by several authors in states of cerebral vasoparalysis, is not predominantly caused by brain edema but by vascular congestion. The clinical aspects of the result are discussed.     

Treatment of acute cerebrovascular disorders

Recent advances in technology have improved stroke diagnosis, reduced the risks and increased the frequency of studies of stroke mechanism. Computer-assisted stroke data bank projects have provided new insights into the frequencies of stroke subtypes and the risks for progression and recurrence. A high frequency of strokes due to infarction remain unexplained despite thorough laboratory investigation. These infarcts of undetermined cause suffer recurrence rates almost as high as cardiogenic embolism, forcing a therapeutic decision even in the absence of a demonstrated cause. Stroke from atherosclerosis is far less common than formerly believed but carries the highest risk of worsening and early recurrence, prompting early treatment to attempt to avoid progression. Duplex and transcranial doppler methods of imaging blood vessels and insonating flow have now made it possible non-invasively to follow the course of atheromatous stenosis, embolism and recanalization, development of collateral flow, and vasospasm in ruptured aneurysms and arteriovenous malformations. Extracranial atheromatous disease may progress rapidly from mild to severe stenosis, stabilize at any point; intracranial collateral is not predicted by the degree of extracranial stenosis. Recanalization of cerebral embolism occurs early. Vasospasm after subarachnoid hemorrhage is common and often severe. Where available, magnetic resonance imaging is preferred to CT scanning for the diagnosis of every form of stroke including hemorrhage.