Vollrath B, Chan P, Findlay M, Cook D
Department of Pharmacology, University of Alberta, Edmonton, Canada.
Cardiovasc Res. 1995 Oct;30(4):619-26.
While it is probable that the cerebrovascular spasm which occurs after subarachnoid haemorrhage results from the action of haemoglobin, the mechanism of that process remains unclear. These studies were thus designed to test the hypothesis that the action of oxyhaemoglobin results from the iron-catalyzed formation of free radicals and subsequent lipid peroxidation resulting in intracellular changes in the second messengers for contraction.
Levels of intracellular calcium and of inositol (1,4,5)-trisphosphate were measured in cultured vascular smooth muscle cells derived from primate cerebral arteries. Contractility of rings of canine cerebral vessels were examined in vitro using standard pharmacological techniques. Vessels in spasm were obtained from the "two haemorrhage" canine model and the presence of vasospasm was confirmed angiographically. In each case, the effects of oxyhaemoglobin and sometimes of free radicals generated from iron salts were examined in the presence and in the absence of free-radical scavenging agents or the iron chelating agent, deferoxamine.
Oxyhaemoglobin produces a slowly-developing sustained contraction of arterial rings which is accompanied by a sustained elevation of intracellular calcium. It also produces a transient but significant elevation of inositol (1,4,5)-trisphosphate, but this is not correlated with the development of sustained constriction. Deferoxamine and the lazaroid compounds U-74389G and U-83836E were effective in preventing the effects of oxyhaemoglobin and free radicals in the models tested, although in vessels in spasm, all effects were smaller.
The present study provides results which are consistent with the hypothesis that the actions of haemoglobin on vascular smooth muscle are mediated by the formation of free radicals which subsequently affect intracellular calcium concentrations. This also implies that agents which impair free radical production or other processes leading to iron-catalyzed lipid peroxidation, are of potential value in cerebrovascular spasm.
虽然蛛网膜下腔出血后发生的脑血管痉挛很可能是由血红蛋白的作用引起的，但该过程的机制仍不清楚。因此，这些研究旨在检验以下假设：氧合血红蛋白的作用源于铁催化的自由基形成以及随后的脂质过氧化，从而导致收缩第二信使的细胞内变化。
测量源自灵长类动物脑动脉的培养血管平滑肌细胞内的钙水平和肌醇（1,4,5）-三磷酸水平。使用标准药理学技术在体外检查犬脑血管环的收缩性。从“两次出血”犬模型中获取痉挛的血管，并通过血管造影证实血管痉挛的存在。在每种情况下，在存在和不存在自由基清除剂或铁螯合剂去铁胺的情况下，检查氧合血红蛋白以及有时铁盐产生的自由基的作用。
氧合血红蛋白会使动脉环产生缓慢发展的持续性收缩，并伴有细胞内钙的持续升高。它还会使肌醇（1,4,5）-三磷酸产生短暂但显著的升高，但这与持续性收缩的发展无关。去铁胺以及拉扎罗类化合物U-74389G和U-83836E在测试模型中可有效预防氧合血红蛋白和自由基的作用，尽管在痉挛的血管中，所有作用都较小。
本研究提供的结果与以下假设一致，即血红蛋白对血管平滑肌的作用是由自由基的形成介导的，自由基随后会影响细胞内钙浓度。这也意味着损害自由基产生或导致铁催化脂质过氧化的其他过程的药物在脑血管痉挛中具有潜在价值。
