Basic Research on Cerebral Vasospasm and Its Prophylaxis

为探讨蛛网膜下腔出血（SAH）后脑血管痉挛的发生机制，探讨治疗和预防SAH后脑血管痉挛的药理学基础，本实验在猴和狗的基底动脉上进行了氧合血红蛋白（oxyHb）、红细胞溶血产物和血液等引起SAH后脑血管痉挛的重要物质的体内和体外实验。所得结果如下。(1)氧合血红蛋白和溶血产物引起的收缩是内皮依赖性的，阿司匹林、吲哚美辛和PG受体拮抗剂ONO 3708可抑制氧合血红蛋白和溶血产物引起的收缩，而超氧化物歧化酶和血栓素A_2合成抑制剂OKY 046则不影响氧合血红蛋白和溶血产物引起的收缩。(2)用免疫放射法测定了OxyHb在培养液中释放的前列腺素（PG）E_2和PGF_2<2alpha>。吲哚美辛可抑制刺激释放。(3)脑池内注射氧合血红蛋白或自体血， 关于我们 通过血管造影确定麻醉犬和猴的最大动脉痉挛。最大的动脉收缩后2小时oxyHb和血液后7天达到收缩的幅度几乎相同。(4)阿司匹林治疗可预防oxyHb引起的血管痉挛，而OKY046无效。Ca^&lt;++&gt;通道阻断剂也能有效防止Hb引起的痉挛。(5)在离体和在体基底动脉上，oxyHb与抗坏血酸孵育后，oxyHb的血管痉挛作用消失，表明oxyHb和溶血产物引起的在体和离体基底动脉收缩作用与血管收缩剂PG有关，而与主要由内皮释放的血栓素A_2无关。应用环氧合酶抑制剂、PG受体拮抗剂和Ca^++阻滞剂或含抗坏血酸的人工液进行脑池灌洗，可能在临床上有效预防SAH后脑血管痉挛的发生。脑池内注射氧合血红蛋白引起的脑血管痉挛将是分析SAH后迟发性血管痉挛机制的有用模型。少

In order to anaylze the mechanism underlying cerebral vasospasm after subarachnoid hemorrhage (SAH) and to determine the pharmacological basis for treatment and prophylaxis of the spasm, experiments were carried out in monkey and dog basilar arteries in vivo and in vitro that were exposed to oxyhemoglobin (oxyHb), erythrocyte hemolysate and blood, quite important substances in generating the cerebral vasospasm. The results obtained are as follows. (1) Contractions caused by oxyHb and hemolysate were endothelium-dependent and suppressed by treatment with aspirin, indomethacin and ONO3708, a PG receptor antagonist, but were unaffected by superoxide dismutase and OKY046, a thromboxane A_2 synthesis inhibitor. (2) OxyHb released significant amounts of prostaglandin (PG) E_2 and PGF_<2alpha> into the bathing media, which were measured by immunoradiological method. The stimulated release was depressed by indomethacin. (3) Intracisternal injections of oxyHb or autologous blood produced a basi … More lar artery spasm in anesthetized dogs and monkeys that was determined angiographically. The maximal arterial constriction was attained 2 hrs after oxyHb and 7 days after blood ; the magnitudes of constriction were almost identical. (4) Treatment with aspirin prevented the vasospasm caused by oxyHb, whereas OKY046 was ineffective. Ca^<++> entry blockers were also effective in preventing the Hb-induced spasm. (5) Incubation of oxyHb with ascorbic acid abolished the vasospastic actions of oxyHb in isolated and in vivo basilar arteries.The findings obtained so far indicate that basilar artery constrictions caused in vivo and in vitro by oxyHb and hemolysate are associated with vasoconstrictor PGs, but not thromboxane A_2, released mainly from the endothelium. Treatment with cyclooxygenase inhbitors, PG receptor antagonists and Ca^<++> entry blockers or cisternal irrigation with artifical fluids containing ascorbic acid may be clinically effective in preventing the genesis of cerebral vasospasm after SAH. Cerebral vasospasm elicited by intracisternal injections of oxyHb would be a useful model for the analysis of mechanisms underlying delayed vasospasm after SAH. Less