Basic Research on Cerebral Vasospasm and Its Prophylaxis

为了分析蛛网膜下腔出血(SAH)后脑血管痉挛的发生机制，确定治疗和预防SAH后脑血管痉挛的药理学依据，在体内外用氧合血红蛋白(OxHb)、红细胞溶血物和血液这三种引起脑血管痉挛的重要物质在猴和狗的基底动脉上进行了实验。取得的结果如下。(1)氧合Hb和溶血物引起的收缩是内皮依赖性的，可被阿司匹林、吲哚美辛和PG受体拮抗剂ONO3708抑制，但不受超氧化物歧化酶和血栓素A_2合成抑制剂OKY046的影响。(2)用放射免疫法测定OxyHb向浴液中释放大量的前列腺素E_2和前列腺素F_2α。吲哚美辛可抑制其刺激释放。(3)脑池内注射氧合Hb或自体血可产生基本的…血管造影术确定麻醉的狗和猴子的大动脉痉挛更多。动脉最大收缩在氧合Hb后2小时和输血后7天达到最大值，收缩程度基本相同。(4)阿司匹林可预防氧合血红蛋白引起的血管痉挛，而OKY046无效。钙通道阻滞剂对Hb诱发的痉挛也有一定的预防作用。(5)氧化Hb与抗坏血酸共同孵育，阻断了氧化Hb对离体和在体基底动脉的血管痉挛作用。结果表明，体内和体外由氧化Hb和溶血素引起的基底动脉收缩与血管收缩药PGs有关，而与主要由内皮释放的血栓素A_2无关。环氧合酶抑制剂、PG受体拮抗剂和钙通道阻滞剂或含抗坏血酸的人工脑池灌洗可有效预防SAH后脑血管痉挛的发生。脑池内注射OxHb诱发的脑血管痉挛是分析SAH后迟发性血管痉挛机制的有用模型。较少

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