Prostaglandin metabolism and prostacyclin in cerebral vasospasm

1. Contractions of isolated human pial arteries, induced either by exposition to hemorrhagic cerebrospinal fluid (CSF) from patients with subarachnoid hemorrhage and cerebral vasospasm or by exposition to noradrenaline, were markedly augmented after preincubation of the vessel segments with the cyclooxygenase inhibitor indomethacin, while serotonin-induced contractions were unaffected. 2. Prostacyclin relaxed human pial arteries contracted by either PGF2 alpha, noradrenaline, serotonin or hemorrhagic CSF. The same though less marked effects were obtained with 6-keto-PGE1. 3. The results support the contention that an intact vascular prostacyclin synthesis is important for the maintenance of a normal cerebrovascular tone, and that disturbances of the prostaglandin metabolism may be a prerequisite for the development of arterial spasm after aneurysmal subarachnoid hemorrhage. Tentatively. 4. a prostacyclin deficiency may be involved in the pathogenesis of delayed cerebral vasospasm after subarachnoid hemorrhage.     

Role of MAPK in cerebral vasospasm

Cerebral vasospasm is the major cause of mortality and morbidity in patients of subarachnoid hemorrhage. Despite intensive studies during the past five decades, the signaling pathways in cerebral arteries that lead to the pathological contraction remain elusive. The complex nature of cerebral vasospasm requires a complex signaling pathway or a group of pathways that may need to interact to initiate and maintain vasospasm. This review explores the possibility that mitogen-activated protein kinase is the elusive signaling pathway responsible for cerebral vasospasm.     

Prevention of delayed cerebral vasospasm after aneurysmal subarachnoid hemorrhage

The delayed cerebral vasoconstriction known as cerebral vasospasm remains a significant cause of permanent neurological deficit and death following aneurysmal subarachnoid hemorrhage despite the best current medical therapies. The mechanism of cerebral vasospasm remains unknown. Several new drugs have been tested in animal models of subarachnoid hemorrhage, and these experimental studies have contributed to a better understanding of the potential mechanisms that lead to cerebral vasospasm. In this article, the authors highlight recent advances in the various treatment procedures for delayed cerebral vasospasm following subarachnoid hemorrhage. (c) 2001 Prous Science. All rights reserved.     

Variations between individuals in cerebrovascular responsiveness

1. Despite extensive research no explanation has been put forward to account for the fact that cerebral arterial spasm complicates the course of disease of many but not all patients suffering from rupture of an intracranial aneurysm. Although vasoactive material in hemorrhagic cerebrospinal fluid (CSF) most probably is of major importance in the pathophysiology of delayed cerebral vasospasm, recent studies have failed to demonstrate a correlation between CSF vasoconstrictor activity and the development of delayed cerebral vasospasm. 2. In the present study the reactivity of isolated human pial arteries to various vasoactive agents [prostaglandin F2 alpha, noradrenaline, serotonin, human plasma and CSF from patients with aneurysmal subarachnoid hemorrhage (SAH)] was investigated. 3. There was a very marked variability in the spectrum of responses between arteries from different individuals with regard to the contractile responses to plasma, hemorrhagic CSF and amines. On the other hand, the contractions produced by prostaglandin F2 alpha and potassium were consistent. 4. The markedly individual profile in terms of reactivity toward vasoactive substances emphasizes the importance of a human cerebral vessel wall factor and may explain the capricious occurrence of cerebral vasospasm after aneurysmal SAH.     

血流动力学动态监测在外伤性蛛网膜下腔出血中的应用

目的探讨脑外伤性蛛网膜下腔出血后血管痉挛引起的血流动力学改变的发生、发展规律及对预后的影响，为临床预防和治疗脑外伤性蛛网膜下腔出血后血管痉挛选择方法及治疗时间窗提供一种新的可靠的检测指标；方法采用经颅多普勒技术对98例脑外伤后蛛网膜下腔出血患者的血流动力学状态进行了动态观察，同时对经颅多普勒在脑外伤后蛛网膜下腔出血患者诊疗中的意义进行了探讨；结果血管痉挛与外伤性蛛网膜下腔出血的程度有关（P〈0．05）；血管痉挛累及的血管种类、数量血管痉挛持续的时间与预后密切相关（γ=0．642，P〈0．05），本研究同时比较了经颅多普勒频谱及血流速度改变对血管痉挛检测的意义，发现频谱改变早于流速改变；结论脑外伤性蛛网膜下腔出血后血管痉挛引起的血流动力学改变是影响外伤性蛛网膜下腔出血患者预后的重要因素。     

西洛他唑治疗动脉瘤性蛛网膜下腔出血的作用机制和临床研究进展

动脉瘤性蛛网膜下腔出血后的迟发性脑缺血是患者严重残疾甚至死亡的主要原因，迟发性脑缺血形成的主要危险因素是脑血管痉挛。西洛他唑是磷酸二酯酶Ⅲ的选择性抑制剂，可舒张血管、抗脂质过氧化、抗血管炎症因子、抑制基底动脉的表型转化和内皮损伤以及抑制腱糖蛋白-C。近年来一系列临床试验表明西洛他唑单用或者联合使用可有效治疗动脉瘤性蛛网膜下腔出血后的脑血管痉挛，进而改善迟发性脑缺血。回顾了西洛他唑在动脉瘤性蛛网膜下腔出血中的作用机制和临床研究，为进一步研究西洛他唑在动脉瘤性蛛网膜下腔出血中的应用提供参考。     

尼莫同治疗蛛网膜下腔出血引起脑血管痉挛的护理研究

目的探讨尼莫同治疗蛛网膜下腔出血诱发脑血管痉挛的护理效果。方法选取本院2010年5月至2013年5月蛛网膜下腔出血诱发脑血管痉挛患者74例,行尼莫同治疗,随机分为两组,37例患者行常规护理为对照组,37例患者行护理干预为观察组,比较两组患者脑血管痉挛复发情况、头痛持续时间、不良反应情况。结果观察组脑血管痉挛复发率、头痛持续时间、不良反应发生率均明显小于对照组,差异均显著(P<0.05)。结论尼莫同治疗蛛网膜下腔出血诱发脑血管痉挛时,护理干预可明显缩短患者的头痛持续时间,降低脑血管痉挛复发率和不良反应发生率。     

小牛血清去蛋白注射液联合尼莫地平治疗创伤性蛛网膜下腔出血后的脑血管痉挛

目的：探讨小牛血清去蛋白注射液联合尼莫地平防治创伤性蛛网膜下腔出血（tSAH）后脑血管痉挛的疗效.方法：将80例创伤性蛛网膜下腔出血患者随机分为治疗组和对照组各40例,两组在常规治疗基础上,均应用尼莫地平注射液10 mg/d静脉泵入（5 ml/h）,1次/d;治疗组加用小牛血清去蛋白注射液1200 mg加入氯化钠注射液250 ml静脉滴注;两组连续治疗14 d.对比两者治疗脑血管痉挛的差异性,用经颅多普勒检测脑血流,并进行统计学分析.结果：治疗组的脑血管痉挛发生率明显低于对照组（P〈0.05）,治疗组的大脑前动脉、大脑中动脉、大脑后动脉的脑血管收缩峰流速低于对照组（P〈0.05）.结论：小牛血清去蛋白注射液联合尼莫地平防治 tSAH后脑血管痉挛疗效优于单纯应用尼莫地平.     

Responses of human and baboon arteries to prostaglandin endoperoxides and biologically generated and synthetic prostacyclin: their relevance to cerebral arterial spasm in man.

1 Isolated strips of human or baboon basilar, middle cerebral, vertebral or common carotid arteries were set up in an isolated organ bath or in a superfusion cascade system. 2 These arteries relaxed to prostacyclin but contracted to prostaglandin endoperoxide (PGH2). 3 Human and baboon isolated arteries also generated prostacyclin from exogenous endoperoxide (PGH2). 4 Human arteries generated prostacyclin 36 h post-mortem but not 40 h post-mortem. The biologically generated prostacyclin relaxed the basilar artery and overcame the contractile effects of PGH2. 5 Thromboxane A2-like activity generated during human platelet aggregation by arachidonic acid caused contractions of the human basilar artery. 6 Prostacyclin reversed contractions of human basilar arteries caused by an unidentified vasoconstrictor factor in cerebrospinal fluid obtained from patients with cerebral arterial vasospasm after subarachnoid haemorrhage following rupture of cerebral arterial aneurysms. 7. The above vasospasm may be due at least in part to disordered physiological control of the calibre of cerebral arteries caused by diminished synthesis of prostacyclin.     

蛛网膜下腔出血后迟发性脑血管痉挛中 TNF-α和NF-кB 的表达变化

目的：检测蛛网膜下腔出血（以下简称 SAH）后迟发性脑血管痉挛中TNF-α和NF-кB的表达变化。方法56只中国白兔随机分成3组：对照组（ n ＝8）：不做枕大池穿刺注血,处死;SAH组（ n ＝24）：在第0天和第2天分二次枕大池注射自体动脉血,分别在第1次注血后第4天、第7天和第14天分三批处死,每组8只;假手术组（ n＝24）：只做枕大池穿刺不注血,第4天、第7天和第14天处死,每组8只。通过计算动脉口径比判断基底动脉痉挛程度,使用免疫组化和免疫蛋白印迹的方法检测迟发性脑血管痉挛中TNF-α和NF-кB的表达变化。结果枕大池注血方法可以造成SAH后迟发性脑血管痉挛模型。 NF-κB 和 TNF-α在注血后第4天表达开始增加（ P ＜0．01）,在第7天达到最高值（ P ＜0．01）,第14天降到对照组水平。结论蛛网膜下腔出血后迟发性脑血管痉挛中NF-κB及 TNF-α表达增加,炎症反应在此过程中起着重要作用。     

盐酸法舒地尔与尼莫地平治疗蛛网膜下腔出血所致脑血管痉挛有效性和安全性的Meta分析

目的:系统评价盐酸法舒地尔与尼莫地平治疗蛛网膜下腔出血所致脑血管痉挛的近期疗效和安全性。方法:计算机检索Cochrane Library、PubMed、EMbase、中国生物医学文献数据库、中国期刊全文数据库、中文科技期刊全文数据库,检索时间从各数据库建库至2011年2月1日;同时辅助其他检索,纳入盐酸法舒地尔与尼莫西平治疗蛛网膜下腔出血所致脑血管痉挛的随机对照试验(RCT)。2名评价者独立评价纳入研究的质量并提取资料,用RevMan 5.0软件进行统计分析。结果:共纳入14篇RCT,合计838例患者。Meta分析结果显示,与尼莫地平比较,盐酸法舒地尔可提高蛛网膜下腔出血所致脑血管痉挛患者的近期疗效[OR=2.69,95%CI(1.76,4.13),P<0.000 01],增加患者大脑的动脉血流速度[MD=12.11,95%CI(6.86,17.36),P<0.000 01],但在减少脑血管痉挛发生方面效果不明显。同时,当前证据显示盐酸法舒地尔并不能减少治疗过程中产生的发热、心悸、颜面发红及头痛等不良反应。结论:盐酸法舒地尔治疗蛛网膜下腔出血所致脑血管痉挛,在提高临床疗效方面优于尼莫地平。由于上述结论存在偏倚的可能性较大,仍需开展设计严密、实施科学的临床研究验证上述结论,为以后的临床应用和科研提供参考。     

尼莫地平对蛛网膜下腔出血后脑血管痉挛模型兔血浆BNP和ET-1表达水平的影响

目的探讨尼莫地平（ND）对蛛网膜下腔出血（SAH）后脑血管痉挛（CVS）兔血浆脑利钠肽（BNP）和内皮素-1（ET-1）含量的影响。方法采用枕大池二次注血法建立兔CVS模型。将40只成年日本大耳白兔随机均分为单纯SAH组（SAH组）和ND治疗组（ND组）。观察两组实验动物的食量及神经功能评分,分别采用酶联免疫吸附测定法（ELISA）和放射免疫法（R IA）检测血浆BNP、ET-1含量,并用经颅多普勒超声（TCD）动态观察两组家兔术前1天和术后第1、4、7、10、14天的基底动脉（BA）血流速度。结果两组家兔注血后第1天血浆BNP水平开始升高（P〈0.05）,ET-1虽较术前有所升高但无统计学意义（P〉0.05）,4-7 d BNP、ET-1均达到高峰（P〈0.05-0.01）,且随着时间的推移有逐渐降低的趋势;ND组BNP及ET-1含量增加的程度明显低于SAH组（P〈0.05-0.01）,但仍显著高于术前对照组（P〈0.05）;两组家兔术后BA血流速度的动态变化趋势与其血浆BNP、ET-1的变化基本一致。结论 SAH后血浆BNP、ET-1含量增多参与了CVS的过程,与CVS的发生、发展密切相关;ND可降低SAH后CVS时血浆BNP、ET-1的水平。     

Possible prophylactic potential of HA1077, a Ca channel antagonist and vasodilator, on chronic cerebral vasospasm

We examined the possible prophylactic potential of HA 1077, a calcium antagonist and vasodilator, on chronic cerebral vasospasm induced in a two-hemorrhage canine model, and also its effects on cerebral hemodynamics. The intravenous infusion of HA1077 3 mg/kg over 30 min twice daily (day 1-day 7) after the first intracisternal injection of 5 ml autologous blood significantly prevented the occurrence of chronic cerebral vasospasm. The mean diameter of the basilar arteries on day 7 was 66.1 ± 1.6% (n = 7) of the baseline before the intracisternal injection of blood, compared to 54.2 ± 1.69% (n = 9) of the baseline in the untreated group (P < 0.01). Bolus intravenous administration of HA1077 (0.1 and 0.3 mg/kg) dose dcpendently increased local cerebral blood flow. Since HA1077 prevents the development of chronic cerebral vasospasm after subarachnoid hemorrhage and improves hemodynamic functions, as manifested by increases in local cerebral blood flow, further study is warranted regarding the possible clinical use of this drug.     

枕大池注入硫酸镁对兔蛛网膜下腔出血后脑血管痉挛的逆转及脑保护作用

目的:研究枕大池注入硫酸镁注射液是否能逆转兔蛛网膜下腔出血后脑血管痉挛以及脑组织损伤。方法:采用兔一次性注血的方法建立蛛网膜下腔出血模型。将30只新西兰大白兔随机分为3组:假手术组、模型组和MgSO4组。前二组于术后24h枕大池注入0.1mL.kg-1生理盐水,后一组注入0.1mL.kg-14%MgSO4。48h后处死兔取基底动脉以及海马组织行病理检查,测定基底动脉管腔横切面积和海马CA1区正常神经元密度。结果:以基底动脉管腔横切面积及海马CA1区正常神经元密度为指标,模型组低于假手术组和MgSO4组(P<0.01),而后二组比较无明显差异(P>0.05)。结论:枕大池注入硫酸镁注射液可能具有逆转兔蛛网膜下腔出血后脑血管痉挛以及脑血管痉挛所致海马神经元损伤作用。     

法舒地尔对蛛网膜下腔出血患者脑血管痉挛的疗效及安全性的系统评价和荟萃分析

目的评价法舒地尔对蛛网膜下腔出血患者脑血管痉挛的疗效及安全性。方法检索中国学术期刊全文数据库、学位论文和会议论文数据库、维普期刊检索、万方数据库、中华医学会数字期刊数据库,以及Pubmed,Cochrane library,OVID和EMBase数据库;以Jadad质量评分标准对文献质量进行评价;以Review Manager 4.2软件进行荟萃分析,全面评价法舒地尔对预防和治疗脑血管痉挛的疗效及安全性。结果 9个研究符合纳入标准,832例患者分别完成了不同指标的试验观察;法舒地尔组患者症状性脑血管痉挛和数字减影血管造影确诊的脑血管痉挛发生比率仅为对照组的48%（OR=0.48,P=0.000 5）和40%（OR=0.40,P=0.000 4）;所有病例脑梗死和脑血管痉挛病例脑梗死的发生比率分别为对照组的50%（OR=0.50,P=0.000 9）和43%（OR=0.43,P=0.000 8）;完全康复患者的比率较对照组增加107%（OR=2.07,P=0.00 9）;与尼莫地平相比,法舒地尔可显著改善治疗2周时患者的意识水平（法舒地尔/尼莫地平：WMD=0.95,P〈0.000 01）;两组不良反应差异无统计学意义（P〉0.05）。结论法舒地尔极大地降低了蛛网膜下腔出血患者脑血管痉挛和脑梗死的发生比率,显著改善了蛛网膜下腔出血患者的临床转归,可显著改善蛛网膜下腔出血患者急性期的意识水平;法舒地尔不良反应的发生比率与尼莫地平相当。     

硫酸镁防治蛛网膜下腔出血后脑血管痉挛的疗效观察

目的:观察硫酸镁防治蛛网膜下腔出血(SAH)后脑血管痉挛(CVS)的疗效。方法:将SAH患者54例,随机分为治疗组(28例)和对照组(26例)。对照组采用脱水、止血等常规疗法;治疗组在常规疗法基础上加用25%硫酸镁15ml加生理盐水250ml,静脉滴注,2次/天;10天后改为1次/天,再用10天停用。采用经颅多普勒(TCD)检测SAH患者脑动脉的收缩峰速度,观察各组CVS发生的情况。结果:治疗组继发CVS 4例(14.3%),对照组13例(50%)。治疗组患者脑动脉的收缩率流速(Vp)较对照组差异极有显著性(P<0.01);且治疗后与治疗前Vp相经差异极有显著性(P<0.01);对照组患者治疗前后的Vp相比差异无显著性(P>0.05)。结论:硫酸镁防治SAH后CVS疗效确切。     

The effect of EGb-761 on morphologic vasospasm in canine basilar artery after subarachnoid hemorrhage

This study investigated the effects of Ginkgo biloba extract (EGb-76l), an anti-oxidant and platelet-activating factor antagonist, on basilar artery vasospasm in an experimental canine subarachnoid hemorrhage model. Morphometric analyses were performed, and serum and cerebrospinal fluid endothelin-l levels were measured by radioimmunoassay. Comparisons were made between treated and untreated groups. Twenty-four mongrel dogs were randomly assigned to three groups. The animals in group 1 (n = 8) were not subjected to subarachnoid hemorrhage and received no treatment. In this group, serum and cerebrospinal fluid endothelin-l levels were measured daily for 8 days. On day 9, the animals were killed and their basilar arteries were excised for histopathological examination. In group 2 (n = 8), subarachnoid hemorrhage was produced using autologous arterial blood, and daily intravenous boluses of saline were administered for the next 8 days. Assessments of endothelin-l levels and the basilar arteries were performed as described for group 1. In group 3 (n = 8), subarachnoid hemorrhage was produced using autologous arterial blood, and daily intravenous boluses of EGb-761 were administered for 8 days. Endothelin-1 levels and the basilar arteries were assessed as described above. The groups' serum endothelin-1, cerebrospinal fluid endothelin-1, and histopathological findings were compared.In group 1, the serum and cerebrospinal fluid endothelin-1 levels did not change significantly over the 8 days, and histopathological examination of the basilar arteries revealed no abnormalities. In group 2, the serum and cerebrospinal fluid endothelin-1 levels increased abruptly and significantly on day 2, and remained high to the end of the study period (day 8). Histopathological examination revealed marked vasospasm. In group 3, the serum and cerebrospinal fluid endothelin-1 levels followed the same pattern observed in group 2; however, the arteries showed significantly less vasospasm than that observed in group 2.The study findings did not provide information about the mechanism of action of the platelet-activating factor-antagonist EGb-761, but they clearly show that this agent decreases morphologic vasospasm in the dog basilar artery.     

尼莫地平2种给药途径治疗蛛网膜下腔出血后脑血管痉挛的疗效观察

目的:观察尼莫地平2种给药途径治疗蛛网膜下腔出血后脑血管痉挛的疗效。方法:68例原发性蛛网膜下腔出血患者,随机分为静脉尼莫地平组和口服尼莫地平组,通过经颅多普勒检测2种给药途径治疗脑血管痉挛后脑血流速度的变化,观察血管痉挛发生率、再出血率及死亡率,评价2种给药途径的疗效。结果:2组患者治疗后21d大脑中动脉血流速度明显改善,同治疗前比较,差异有显著性(P<0.05),治疗后21d神经功能缺损评分有显著性差异(P<0.05),且静脉尼莫地平组神经功能改善最佳,但2组无显著性差异(P>0.05);2组患者脑血管痉挛发生率、死亡率及再出血发生率明显降低,组间比较无显著性差异(P>0.05)。2组不良反应均较轻微。结论:尼莫地平治疗蛛网膜下腔出血疗效确切,口服及静脉给药疗效相当。