NITROXIDERGIC CEREBROVASCULAR TONE DURING ANESTHESIA

直接或间接地操纵脑血管张力，是有神经损伤风险患者麻醉和围手术期护理的重要组成部分。这个项目的总体目标是更好地表征在健康和疾病中维持人类脑血管张力的控制机制。这些知识将极大地促进旨在保护大脑免受永久性损伤的策略。除了回答机制问题外，拟议的研究还将有助于制定麻醉和手术期间脑血管阻力的急性药理学操作方案，在脑动脉通路可用的情况下。这是及时的，因为血管内手术越来越频繁地用于各种脑血管疾病。脑血流（CBF）主要受三种机制调节：一氧化氮（NO）（主要通过cGMP）、前列腺素（主要通过cAMP）和atp敏感的K+通道。该项目解决了两个具体问题：(1)NO在多大程度上影响静息状态下的人类脑血管张力？(2)神经元型一氧化氮合酶与内皮型一氧化氮合酶（NOS）在影响静息血管张力方面的相对重要性是什么？我们的主要假设是，在人类中，内皮生成的NO是一个主要的调节影响。将进行平行的体内（人类和非人类灵长类动物）和体外实验。体内研究将采用颈动脉内输注药物。颈动脉内输注可以在相对独立于全身副作用的情况下评估药物的脑血管作用。临床研究将在对功能正常和血管造影正常的大脑半球进行脑血管造影时进行。以狒狒为对象的动物实验将与临床研究同时进行。体外研究将在狒狒解剖时收获的颅内血管上进行。这种人类和灵长类动物的平行模型是一种独特而有力的方法，可以探索各种激动剂和拮抗剂的全剂量反应范围，并允许设计利用有限临床受试者供应的最佳方案。此外，体外研究将提供对调节脑血管张力的分子和细胞机制的见解。如果内皮NO是人类脑血管张力的主要决定因素，使用神经元NOS抑制剂的神经保护不应损害组织灌注，动脉内NO供体可能有助于缺血性脑损伤的脑灌注。

Manipulation of cerebrovascular tone, either directly or indirectly, is an important component of anesthetic and peri-operative care in patients at risk for neurologic injury. This project has the general aim to better characterize the control mechanisms for maintenance of human cerebrovascular tone in health and disease. Such knowledge would greatly facilitate strategies aimed at protecting the brain from permanent damage. In addition to answering mechanistic questions, the proposed studies will also be useful in the development of protocols for acute pharmacologic manipulation of cerebrovascular resistance during anesthesia and surgery in cases where cerebral arterial access is available. This is timely because there is an increasingly frequent use of endovascular surgery for a wide variety of cerebrovascular diseases. It is believed that cerebral blood flow (CBF) is regulated by three main mechanisms: nitric oxide (NO) (predominantly via cGMP), prostaglandins (predominantly via cAMP) and ATP-sensitive K+ channels. This project addresses two specific questions: (1) To what extend does NO influence resting human cerebrovascular tone? (2) What is the relative importance of neuronal versus endothelial nitric oxide synthase (NOS) in influencing resting vascular tone? Our primary hypothesis is that in humans, enothelially-generated NO is a major regulatory influence. Parallel in-vivo (in humans and non-human primates) and in-vitro experiments will be done. In-vivo studies will employ intracarotid infusion of drugs. Intracarotid infusion enables assessment of cerebrovascular effects of a drug in relative isolation from its systemic side-effects. The clinical research will be conducted during cerebral angiography of functionally and angiographically normal cerebral hemispheres. Animal experiments, in baboons, will be conducted in parallel with the clinical research. In vitro studies will be undertaken on intracranial vessels harvested at autopsy from baboons. This parallel model of human and primate is a unique and powerful approach for exploring he full dose-response range of various agonists and antagonists as well as allowing design of optimal protocols utilizing a limited supply of clinical subjects. In addition, in-vitro studies will provide the insight into molecular and cellular mechanisms that regulate cerebrovascular tone. If endothelial-NO is a major determinant of human cerebrovascular tone, neuroprotection using neuronal NOS inhibitors should not compromise tissue perfusion, and intra-arterial NO donors may be useful in manipulation of cerebral perfusion in ischemic brain injury.