Endothelial dysfunction in a primate model of cerebral vasospasm
Endothelial dysfunction in a primate model of cerebral vasospasm
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DOI：
10.3171/jns.2004.100.2.0287
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发表时间：
2004-02-01
影响因子：
4.1
通讯作者：
Oldfield, EH
中科院分区：
文献类型：
--
作者：
Iuliano, BA;Pluta, RM;Oldfield, EH
Object.尽管在实验和临床研究中都报道了内皮血管动力控制的异常，但蛛网膜下腔出血（SAH）后发生的内皮功能障碍的机制仍不清楚。由于之前没有对SAH或脑血管痉挛后脑血管内皮功能的体内研究，作者在建立的SAH后血管痉挛灵长类动物模型中研究了内皮依赖性反应。通过检查颈动脉内注射各种已知通过内皮起作用的药物对血管的反应来评估内皮功能。选择具有快速全身清除率的药物，使其药理作用仅限于颈动脉内输注后的脑循环。使用了17只成年雄性食蟹猴。在右侧大脑中动脉周围放置蛛网膜下腔凝块后7、14和21天，在对照动物和SAH动物中检查脑血管内皮依赖性反应。在5分钟的颈动脉内输注5%葡萄糖载体、乙酰胆碱、组胺、缓激肽在对照组动物中，颈动脉内输注乙酰胆碱产生了显著的与葡萄糖溶剂对照输注相比，CBF增加（7.8 +/- 9.5%），CVR降低9.3 +/- 8.7%。SAH后7天，动物对乙酰胆碱的反应消失，特别是动脉造影证实存在血管痉挛的动物亚组。在对照组动物中，输注钙霉素未引起CBF或CVR的显著变化，但在SAH后7天的动物和血管痉挛动物中，CBF显著降低，CVR增加。组胺或缓激肽的输注对CBF或CVR没有显著影响。颈动脉内注入乙酰胆碱，而不是组胺、缓激肽或钙霉素，在正常灵长类动物的血管系统中产生了可测量的生理反应。蛛网膜下腔出血后发生的脑血管痉挛产生的病理生理效应与Furchgott和Zawadzki的体外实验中显示的内皮剥脱相似，其中乙酰胆碱通过激活平滑肌细胞上的受体使血管收缩。与对照动物相比，血管痉挛动物对乙酰胆碱和Calcimycin的血管反应的变化提供了证据，表明内皮功能障碍在SAH后血管痉挛的发展和/或维持中起着关键作用。
Object. Although abnormalities in the control of endothelial vasomotility have been reported in both experimental and clinical studies, the mechanism of the endothelial dysfunction that occurs following subarachnoid hemorrhage (SAH) remains unclear. Because of the absence of previous in vivo studies of endothelial function in cerebral vessels in response to SAH or cerebral vasospasm, the authors investigated endothelium-dependent responses in an established primate model of vasospasm after SAH. Endothelial function was assessed by examining vascular responses to intracarotid injections of various drugs known to act via the endothelium. Drugs that have a rapid total body clearance were selected so that their pharmacological effects would be limited to the cerebral circulation after an intracarotid infusion.Methods. Seventeen adult male cynomolgus monkeys were used. Cerebrovascular endothelium-dependent responses were examined in control animals and in animals with SAH 7, 14, and 21 days after placement of a subarachnoid clot around the right middle cerebral artery. Cortical cerebral blood flow (CBF) and cerebrovascular resistance (CVR) were recorded continuously during 5-minute intracarotid infusions of 5% dextrose vehicle, acetylcholine, histamine, bradykinin, or Calcimycin.In control animals the intracarotid infusion of acetylcholine produced a significant (7.8 +/- 9.5%) increase in CBF and a 9.3 +/- 8.7% reduction in CVR in comparison with a control infusion of dextrose vehicle. The responses to acetylcholine disappeared in animals 7 days post-SAH, specifically in the subset of animals in which arteriography confirmed the presence of vasospasm. Infusion of Calcimycin produced no significant changes in CBF or CVR in control animals, but resulted in a significant reduction in CBF and increase in CVR in animals 7 days after SAH and in animals with vasospasm. An infusion of histamine or bradykinin had no significant effect on CBF or CVR.Conclusions. An intracarotid infusion of acetylcholine, but not one of histamine, bradykinin, or Calcimycin, produced a measurable physiological response in the normal primate cerebrovasculature. Cerebral vasospasm that occurred after SAH produced a pathophysiological effect similar to the endothelial denudation shown in the in vitro experiments of Furchgott and Zawadzki, in which acetylcholine constricted the vessels via activation of receptors on smooth-muscle cells. Changes in vascular responses to acetylcholine and Calcimycin in animals with vasospasm, compared with control animals, provide evidence that endothelial dysfunction plays a key role in the development and/or sustenance of vasospasm after SAH.