PATHOPHYSIOLOGY OF CHRONIC CEREBRAL VASOSPASMS

大约30,000名北美人患有颅内动脉瘤破裂 每年。因为在所有形式的颅内动脉瘤中， 出血，几乎是独一无二的，在血管上沉积了大量的血块 在基底传导动脉的外膜一侧，常为 延迟性、持续性动脉收缩的原因称为 血管痉挛。血管痉挛可能非常严重，以至于血管实际上可能 闭塞和远端缺血可导致延迟性脑梗塞 --第二杆。大约三分之二的破裂动脉瘤患者会 如果出现中度到重度的血管造影血管痉挛 血管造影术在最初出血后一周左右。大约一半的人 这些患者会出现延迟性缺血的临床症状。这个 近年来，这种现象的死亡率稳步下降， 广泛避免脱水和抗纤溶药物。在……里面 此外，钙拮抗剂、高血压和高容量血症可能有 起到了有益的作用。然而，目前约有15%的患者 仍然会因血管痉挛而死亡或严重受损。脑缺血的证据 脑梗塞在大约30%的死亡病例中被发现 如果动脉瘤在最初几天内存活下来，就会破裂。 我们的长远目标是： (1)预防蛛网膜下腔出血后血管痉挛； (2)已建立的血管痉挛的成功治疗。 该项目的具体目标是确定： (1)脑动脉壁细胞骨架变化的时程 猕猴蛛网膜下腔出血后的动脉；(2)发病机制和 预防氧合血红蛋白诱发的猴脑血管痉挛； 血管痉挛发生和发展过程中动脉壁的生化变化 (4)细胞内游离钙浓度的时间进程 长时间培养的血管平滑肌细胞的变化 暴露于氧合血红蛋白以及钙进入的机制是否 对正常钙通道拮抗剂敏感；(5) 蛋白激酶C在脑血管痉挛发生中的激活； (6)细胞内钙升高的来源与损伤有关。 通过氧合血红蛋白；(7)如果自由基损伤分离的脑血管 平滑肌细胞主要来自内或外；(8) 自由基破坏表面膜或离子的脂类成分 经络；(9)痉挛灵长类动物腔内气囊扩张 脑动脉导致血管即刻和持久的改善 是否有任何不利的结构性变化 动脉壁；(10)鞘内尿激酶是否能预防慢性脑血管疾病 灵长类动物模型中的血管痉挛。

About 30,000 North Americans have rupture of an intracranial aneurysm each year. Because aneurysmal rupture, among all forms of intracranial bleeding, almost uniquely deposits a large volume of blood clot on the adventitial side of the basal conducting arteries, it is frequently the cause of a delayed onset, long-lasting arterial constriction known as vasospasm. Vasospasm can be so severe that the vessels may actually be occluded and distal ischemia can result with attendant delayed infarction - the second stroke. About two-thirds of ruptured aneurysm patients will show moderate to severe degrees of angiographic vasospasm if subjected to angiography a week or so after the initial hemorrhage. About half of these patients will develop clinical signs of delayed ischemia. The death rate from this phenomenon has fallen steadily in recent years with the widespread avoidance of dehydration and antifibrinolytic agents. In addition, calcium antagonists, hypertension and hypervolemia may have exerted a beneficial effect. Currently, however, about 15% of patients will still die or be severely damaged by vasospasm. Evidence of ischemic cerebral infarction is noted in about 30% of the fatal cases of aneurysmal ruptures if they survive past the initial few days. Our long-term objectives are: (1) prevention of vasospasm after subarachnoid hemorrhage; (2) the successful treatment of established vasospasm. The specific aims of the project are to determine: (1) time course of cytoskeletal changes in arterial walls of cerebral arteries after subarachnoid hemorrhage in monkeys; (2) pathogenesis and prevention of oxyhemoglobin-induced cerebral vasospasm in monkeys; (3) biochemical changes in arterial vessel wall as vasospasm develops and abates; (4) time course of intracellular free calcium concentration changes in cultured vascular smooth muscle cells following prolonged exposure to oxyhemoglobin and if the mechanism of calcium entry is sensitive to normal antagonists of calcium channels; (5) role of activation of protein kinase C in production of cerebrovascular spasm; (6) the source of increased intracellular calcium correlated with damage by oxyhemoglobin; (7) if free radicals damage isolated cerebrovascular smooth muscle cells primarily from the inside or outside; (8) whether free radicals damage lipid components of surface membrane or ion channels; (9) if transluminal balloon dilatation of spastic primate cerebral arteries results in immediate and enduring improvement in vessel caliber and whether there is any adverse structural change in the arterial wall; (10) if intrathecal urokinase can prevent chronic cerebral vasospasm in a primate model.