Iuliano Brian A, Pluta Ryszard M, Jung Carla, Oldfield Edward H
Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, USA.
J Neurosurg. 2004 Feb;100(2):287-94. doi: 10.3171/jns.2004.100.2.0287.
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.
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.
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.
尽管在实验研究和临床研究中均已报道内皮血管舒缩功能控制存在异常，但蛛网膜下腔出血（SAH）后发生的内皮功能障碍机制仍不清楚。由于既往缺乏关于SAH或脑血管痉挛后脑血管内皮功能的体内研究，作者在一个已建立的SAH后血管痉挛灵长类动物模型中研究了内皮依赖性反应。通过检查对经颈动脉注射各种已知通过内皮起作用的药物的血管反应来评估内皮功能。选择具有快速全身清除率的药物，以便在颈动脉内输注后其药理作用仅限于脑循环。
使用17只成年雄性食蟹猴。在对照动物以及在右大脑中动脉周围放置蛛网膜下腔血凝块后7、14和21天的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、缓激肽或钙霉素期间，连续记录皮质脑血流量（CBF）和脑血管阻力（CVR）。在对照动物中，与输注葡萄糖载体相比，颈动脉内输注乙酰胆碱使CBF显著增加（7.8±9.5%），CVR降低9.3±8.7%。SAH后7天的动物中，对乙酰胆碱的反应消失，特别是在动脉造影证实存在血管痉挛的动物亚组中。在对照动物中，输注钙霉素对CBF或CVR无显著影响，但在SAH后7天的动物和有血管痉挛的动物中导致CBF显著降低和CVR增加。输注组胺或缓激肽对CBF或CVR无显著影响。
颈动脉内输注乙酰胆碱，但组胺、缓激肽或钙霉素则不然，在正常灵长类动物脑血管系统中产生了可测量的生理反应。SAH后发生的脑血管痉挛产生了与Furchgott和Zawadzki体外实验中所示内皮剥脱相似的病理生理效应，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，有血管痉挛的动物对乙酰胆碱和钙霉素的血管反应变化提供了证据，表明内皮功能障碍在SAH后血管痉挛的发生和/或维持中起关键作用。
