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.     

Enhanced reactivity to vasopressin in rat basilar arteries during vasospasm after subarachnoid hemorrhage

Subarachnoid hemorrhage increases the plasma level of vasopressin, a well-known vasoconstrictor. We examined the sensitivity to vasopressin in rat basilar artery after subarachnoid hemorrhage using a rat subarachnoid hemorrhage model. Vasospasm was observed 1-2 days after subarachnoid hemorrhage induction, and the contractile response to vasopressin in rat basilar arteries was assessed. The concentration-response curve for vasopressin in subarachnoid hemorrhage (1 day) rats shifted leftward compared with that of control rats. The concentration-response curve for vasopressin V(1) receptor agonist also shifted leftward and upward compared with that of control rats. The concentration-response curve for vasopressin was inhibited not by vasopressin V(2) receptor antagonist but by vasopressin V(1) receptor antagonist. Thus, it was demonstrated that the vasoconstricting effect of vasopressin was significantly enhanced in the vasospasm phase after subarachnoid hemorrhage.     

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.     

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。     

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。     

Hypersensitivity to hydroxyl radicals in rat basilar artery after subarachnoid hemorrhage

Vasospasm after subarachnoid hemorrhage (SAH) is a serious complication and we have been investigating the relationship between vasoconstrictors and vasospasm after SAH. The present study was designed to investigate the vasocontractile responses to reactive oxygen species in isolated rat basilar arteries from the control and experimental SAH rats. Contractile responses to hydroxyl radicals in basilar arteries from SAH rats were 3-6-fold higher than those in control rats. The present results clearly indicate that hypersensitivity to hydroxyl radicals may contribute to the vasospasm after SAH.     

Effective improvement of the cerebral vasospasm after subarachnoid hemorrhage with low-dose nitroglycerin

In the rabbit subarachnoid hemorrhage (SAH) model, the sensitivity of spastic basilar arteries to nitric oxide (NO) was enhanced whereas the endothelial function to release/produce NO became impaired, as described previously. We assumed from these results that low-dose NO might selectively dilate spastic arteries without influencing normal or systemic blood vessels; therefore, we investigated whether exogenous low-dose NO effectively improves cerebral vasospasm. Low-dose NO was derived from a small size of the tape containing nitroglycerin, which is not invasive and is clinically available. The experimental SAH was induced by injecting autologous blood into the cisterna magna of the rabbit. Experiments were performed on the following three groups: (a) SAH group with nitroglycerin tape (nitroglycerin group), (b) SAH group with placebo tape (placebo group), and (c) saline group injected with saline instead of blood. The tape containing 0.675 mg nitroglycerin was applied once daily for 2 days onto the skin area of the rabbit's ear. Angiograms were performed once before cisternal injection of blood and/or saline and again on day 2. On day 2 the basilar artery was isolated and sliced into 2-mm ring preparations. Relaxations of the basilar artery to acetylcholine, sodium nitroprusside, and calcium ionophore A23187, as well as the contractile responses to serotonin and endothelin- 1, were measured. The diameter of the basilar artery on day 2 was reduced to 69.6+/-2.2% (n = 7) before the injection of autologous blood. The angiographic vasospasm of the basilar artery was partially but significantly (p<0.0001) improved to the percentage diameter of 89.4+/-1.4% (n = 7) by the application of low-dose nitroglycerin, which did not affect the systemic blood pressure and heart rate. In the basilar artery preparations harvested from SAH rabbits on day 2, the impaired acetylcholine-induced endothelium-dependent relaxation was partially but significantly (p<0.001) improved in the nitroglycerin group. However, this group remained unaffected in the increased sensitivity to nitroglycerin and the contractile responses to serotonin and endothelin-1. Low-dose nitroglycerin tape effectively improved the cerebral vasospasm after SAH without any significant changes in the systemic circulation and would be one of the useful and noninvasive treatments for cerebral vasospasm. The results seem to be partially affected by the effective dilation of the spastic artery and the improvement of the impaired endothelium-dependent relaxation with low-dose NO.     

Effect of recombinant human erythropoietin on cerebral ischemia following experimental subarachnoid hemorrhage

Erythropoietin exerts a neuroprotective effect during cerebral ischemia. We investigated the effect of systemic administration of recombinant human erythropoietin in a rabbit model of subarachnoid hemorrhage-induced acute cerebral ischemia. The animals were divided into three groups: group 1, subarachnoid hemorrhage; group 2, subarachnoid hemorrhage plus placebo; group 3, subarachnoid hemorrhage plus recombinant human erythropoietin (each group, n=8). Experimental subarachnoid hemorrhage was produced by injecting autologous blood into the cisterna magna. Treatment with recombinant human erythropoietin and placebo was started 5 min after subarachnoid hemorrhage and was continued every 8 h for 24 h. Before the animals were killed, erythropoietin concentration was measured in the cerebrospinal fluid. The rabbits were killed 24 h after subarachnoid hemorrhage and ischemic brain injury was histologically evaluated. In group 3, the concentration of erythropoietin in the cerebrospinal fluid was significantly increased and a significant reduction in cortical necrotic neuron count was also observed. These findings may encourage the use of erythropoietin in the treatment of cerebral ischemia that often occurs in the early stage of subarachnoid hemorrhage.     

动脉瘤性蛛网膜下腔出血后脑血管痉挛67例临床分析

目的 分析脑脊液置换联合尼莫地平防治动脉瘤性蛛网膜下腔出血（aSAH）后脑血管痉挛（CVS）的效果。方法 aSAH患者67例随机分为两组,对照组常规治疗,观察组在常规治疗基础上行脑脊液置换术。观察两组DCVS和继发性脑梗死的发生率及临床疗效及大脑中动脉平均血流速度。结果 观察组总有效率明显高于对照组,大脑中动脉流速明显低于对照组（P〈0.05）。结论 脑脊液置换联合尼莫地平可明显降低动脉瘤性蛛网膜下腔出血患者迟发型脑血管痉挛的发生,降低大脑中动脉的平均血流速度。     

Protein kinase cdelta and alpha are involved in the development of vasospasm after subarachnoid hemorrhage

We have previously shown the enhanced activity of protein kinase C in the membrane fraction of the canine vasospastic artery after subarachnoid hemorrhage, which increased with progression of angiographic vasospasm. This study examined identification of protein kinase C isoforms in the canine basilar artery, and the changes in expression and/or translocation of each isoform during the development of vasospasm. Vasospasm was produced by using the "two-hemorrhage" canine model in the basilar artery, and angiographic progression of vasospasm was assessed consecutively. Two isoforms, protein kinase Calpha and delta were identified in basilar arteries by Western blotting. Densitometric analysis showed that the expression of protein kinase Cdelta in the membrane fraction was significantly increased in the earlier stage, and protein kinase Calpha was increased later as vasospasm progressed. These results indicate that protein kinase Cdelta and alpha isoforms may play a significant role in the development and maintenance of vasospasm.     

Heme oxgenase-1 gene induction and the mechanism in the rat vasospasm model

Using fluorescent differential display and quantitative reverse-PCR, we found in the rat vasospasm model that heme oxygenase-1 messenger RNA was induced in basilar artery. Intracistemal injection of antisense OH-1 oligodeoxynucleotide significantly reduced HO-1 mRNA and HO-1 protein levels and enhanced angiographic vasospasm. Thus, we demonstrate that HO-1 induction may play a important role in the resolution of delayed vasospasm after subarachnoid hemorrhage.     

动脉持续灌注罂粟碱对兔脑血管痉挛的实验研究

目的　观察动脉持续灌注罂粟碱对蛛网膜下腔出血后脑血管痉挛的作用。方法　日本大耳白兔用“二次枕大池注血法”制作症状性脑血管痉挛模型。经一侧椎动脉用微量泵持续灌注罂粟碱。结果　持续灌注罂粟碱 2天、5天基底动脉造影直径和神经系统损害症状级别与治疗前比较有明显改善 (P <0 0 1) ;对照组无明显改善 (P >0 0 5 )。对照组基底动脉、脑组织结构改变明显 ,治疗组基本正常。结论　动脉持续灌注罂粟碱有预防迟发性脑血管痉挛作用。     

Participation of vasopressin in the development of cerebral vasospasm in a rat model of subarachnoid haemorrhage

1. Previous studies have suggested the involvement of arginine vasopressin (AVP) and inflammation in the development of cerebral vasospasm after subarachnoid haemorrhage (SAH). The aim of the present study was to clarify the role of AVP in the arterial narrowing following cerebral haemorrhage by examining the effect of SR 49059 (a V(1) receptor antagonist) on the diameter of rat basilar artery exposed to SAH. The effect of the 5-lipoxygenase inhibitor ZM 230487 on AVP-induced contraction of rat basilar arteries was also investigated. 2. After 1 h and 2 days from SAH induction, brains were removed and pictures of the basilar arteries were taken. The external diameter of the basilar artery was measured in the presence and absence of SR 49059 (1 mg/kg, i.v.). For in vitro experiments, the basilar arteries isolated from control and SAH rats (at 1 h and at 2 days from SAH induction) were cut into spiral preparations and the AVP (0.3 nmol/L)-induced contraction in the presence of ZM 230487 was investigated. Each group analysed (i.e. control, SAH 1 h and SAH 2 days) consisted of eight rats. 3. The diameter of rat basilar arteries decreased by 43 and 25% at 1 h and 2 days from SAH induction, respectively, compared with control. The administration of SR 49059 significantly reduced cerebral vasospasm. After SAH induction, the diameter of the basilar artery in SR 49059-treated groups decreased by only 22% (at 1 h) and by 3% (at 2 days) compared with the control group (P < 0.01). In basilar arterial strips, ZM 230487 attenuated the vasopressin-induced contraction in both control and SAH groups. However, SAH groups showed a significant resistance of the AVP-induced contraction in the presence of ZM 230487 compared with control (P < 0.05). 4. The results suggest that the cerebral vasospasm in SAH rats is due, at least in part, to endogenous AVP and may involve an increase in the activity of 5-lipoxygenase. SR 49059 may represent a potential therapeutic strategy for the treatment of cerebral vasospasm.     

Effects of deferoxamine and sympathectomy on endothelin-1-induced contraction and acetylcholine—Induced relaxation following subarachnoid hemorrhage in carotid artery

The role of endothelium-related factors in the pathogenesis of cerebral vasospasm after subarachnoid hemorrhage (SAH) has gained interest since the discovery of EDRF and of endothelin-1 (ET-1). The effect of SAH and both treatment of deferoxamine (DFO) and sympathectomy on endothelium-dependent vasodilation and ET-1-induced vasoconstriction of isolated rabbit carotid artery was examined using an isometric tension recording method. Thirty-five rabbits were divided into four groups: control animals, 7 days after SAH, treatment with DFO after SAH for 7 days and sympathectomy after SAH. Acetylcholine (10⁻⁸ to 10⁻⁵ M) was used to evoke concentration-dependent vasodilation of isolated arterial rings previously contracted by 10⁻⁶ M phenylephrine. In the animals killed 7 days after SAH, acetylcholine-induced relaxation was suppressed and the degree of relaxation of this group was 50% of the initial contractile tone in response to the 10⁻⁵ M acetylcholine. These relaxant responses did not return to control values in carotid arteries obtained from animals treated with DFO and subjected to sympathectomy. In isolated carotid arteries, ET-1 (10⁻¹⁰ to 10⁻⁸ M) produced concentration-dependent contractions. These contractile responses were significantly enhanced in animals 7 days after SAH compared with controls and did not return to control values in carotid arteries obtained from animals both treated with DFO and sympathectomized for 7 days after SAH. The present experiments suggest that impairment of endothelium-dependent vasodilation and the hyperreactivity of ET-1 of the carotid artery as well as cerebral arteries may be involved in the pathogenesis of cerebral vasospasm. Both treatment with DFO and sympathectomy during the chronic stage for vasospasm after SAH did not affect these vascular responses of the extradural part of the carotid artery to ET-1 and acetylcholine.     

蛛网膜下腔出血行腰椎穿刺置管持续稳压引流的疗效分析

目的探讨腰椎蛛网膜下腔置管持续引流对蛛网膜下腔出血(SAH)的疗效。方法:对63例SAH患者进行治疗:治疗组(33例)实施腰椎蛛网膜下腔置管持续流脑脊液,对照组(30例)行间断腰椎穿刺放脑脊液。结果:治疗组头痛或轻程度,痊愈率明显优于对照组,脑血管痉挛、脑积水发生率明显低于对照组,未增加再出血、脑疝发生率及病死率。结论:腰椎蛛网膜下腔置管持续稳压引流脑脊液是一种安全、有效的治疗SAH的方法。     

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。     

脑脊液置换联合尼莫地平、地塞米松鞘内注射治疗蛛网膜下腔出血的疗效分析

目的研究脑脊液置换联合尼莫地平、地塞米松鞘内注射治疗蛛网膜下腔出血（SAH）的治疗作用。方法将127例SAH患者随机分为试验组和对照组;对照组应用镇静、止痛、药物（EACA、尼莫地平片）等常规治疗方法,试验组在常规治疗的基础上,应用腰穿脑脊液置换和鞘内注射尼莫地平、地塞米松。结果SAH的头痛症状以及脑积水、蛛网膜粘连、脑血管痉挛等主要并发症的发生率、死亡率,试验组明显少于对照组,经统计学处理,有统计学差异。结论脑脊液置换联合尼莫地平、地塞米松鞘内注射治疗蛛网膜下腔出血,可明显降低SAH主要并发症的发生率和死亡率,其方法简便,效果可靠,有非常实用的临床价值。     

外源性L-精氨酸对大鼠脑血管痉挛的影响

目的：探讨L-精氨酸(L-Arg)对蛛网膜下腔出血(SAH)所致脑血管痉挛(CVS)的影响。方法：应用脑底动脉环血管内穿刺法建立大鼠SAH模型，将动物分为假手术组(SO组)、SAH组和SAH L-Arg组。动态检测24h内项叶皮层局部脑血流量(rCBF)，测量基底动脉(BA)管径，并测定不同时点脑组织内皮素—1(ET—1)含量。结果：假手术组对各项指标无显著影响。SAH组术后rCBF迅速降低，并持续24h；SAH后BA管径明显缩小；脑组织ET-1含量逐渐增加。与SAH组比较，SAH L—Arg组rCBF下降的速度减慢、程度减轻，BA管径缩小的程度减轻，脑组织ET—l含量增加的幅度减小。结论：L-Arg通过增加NO产生、抑制ET—1生成而缓解SAH后CVS。