NITRIC OXIDE AND IN VIVO BRAIN ARTERIOLAR RELAXATION

描述：(改编自应用程序)底层机制 促进低氧、低血糖和低血糖时脑血流量的增加 人们对高碳酸血症的认识还不完全。一种内源性血管扩张因子 似乎与此有关的是一氧化氮。建议的实验是 旨在确定一氧化氮相关的机制 脑血管扩张和部位(血管内皮或血管周围) 合成了一氧化氮。在这些研究中，在麻醉的大鼠中， 将使用闭合颅窗活体显微镜系统。这 允许测量软脑膜小动脉的直径变化和 给药给药到大脑表面。考察……的作用 一氧化氮在低氧或低血糖的血管扩张反应中的作用 随着病情的加重，一氧化氮合酶抑制剂(L-NNA) 弥漫着。在对照中，L-NNA将被其非活性对映体取代， D-NNA。此外，在缺氧和低血糖中，一氧化氮的作用 将与其他已知的独立一氧化氮进行评估 血管扩张刺激、腺苷释放或β肾上腺素能受体激活。至 证实cGMP在小动脉水平的作用，推测是鸟苷 环化酶或cGMP依赖的蛋白激酶抑制剂将被泛滥。这个 一氧化氮促进大鼠脑血管扩张的机制 缺氧、低血糖和高碳酸血症将分为2类 类：允许的和活动的元素。对于允许的，L-NNA将 与一氧化氮供体(SNAP)或cGMP类似物或cAMP共灌流 磷酸二酯酶抑制剂。以测试允许的行为是否 NO/cGMP与K通道有关，其他实验将包括一氧化氮合酶 抑制剂和cGMP类似物与选择性K+通道阻滞剂共灌流。 导致NO生成增加的潜在机制(活性因素) 将会被检查。这些研究包括关于兴奋作用的研究。 氨基酸的释放。将进行评估的一氧化氮生产地点包括 内皮(形成缺氧和低血糖)和血管周围结构。 对于内皮细胞，将使用光/染料方法。适用于血管周围 研究，血管扩张反应将在存在的情况下评估 神经元活动的抑制剂，河豚毒素或一种新的 神经元型一氧化氮合酶(ARL 17477AR)。这些实验应该 增加我们对血管扩张机制的了解 临床感兴趣的扰动如缺氧、低血糖和 提高我们对一氧化氮在高碳酸血症中作用的认识 脑血管扩张功能。

DESCRIPTION: (Adapted from the application) The underlying mechanisms promoting increases in cerebral blood flow during hypoxia, hypoglycemia and hypercapnia are not fully understood. One endogenous vasodilating factor that appears to be involved is nitric oxide. The proposed experiments are designed to identify the mechanisms of nitric oxide related cerebrovasodilation and the site (endothelium or perivascular) where that nitric oxide is synthesized. For these studies, in anesthetized rats, a closed cranial window intravital microscopy system will be used. This permits the measurement of diameter changes in pial arterioles and the administration of agents to the brain surface. To examine the role of nitric oxide in the vasodilatory responses to hypoxia or hypoglycemia, of increasing severity, the nitric oxide synthase inhibitor (L-NNA) will be suffused. In controls, L-NNA will be replaced by its inactive enantiomer, D-NNA. Furthermore, in hypoxia and hypoglycemia, the role of nitric oxide will be evaluated in relation to other known nitric oxide independent vasodilating stimuli, adenosine release or beta adrenoceptor activation. To corroborate the cGMP role at the arteriolar level, putative guanylate cyclase or cGMP-dependent protein kinase inhibitors will be suffused. The mechanisms through which nitric oxide promotes cerebrovasodilation in hypoxia, hypoglycemia and hypercapnia will be divided into 2 general classes: permissive and active elements. For permissive, L-NNA will be co-suffused with a nitric oxide donor (SNAP) or a cGMP analog or a cAMP phosphodiesterase inhibitor. To test whether the permissive action of NO/cGMP relates to K-channels, additional experiments will include NOS inhibitor and cGMP analog co-suffusions with selective K+ channel blockers. Potential mechanisms leading to increased NO generation (active factors) will be examined. These include studies concerning the role of excitatory amino acid release. The nitric oxide production sites to be evaluated are endothelium (form hypoxia and hypoglycemia) and perivascular structures. For endothelium, the light/dye method will be used. For perivascular studies, vasodilatory responses will be assessed in the presence of an inhibitor of neuronal activity, tetrodotoxin or a novel inhibitor of the neuronal nitric oxide synthase (ARL 17477AR). These experiments should increase our understanding of the mechanisms involved in the vasodilatory responses of perturbations of clinic interest like hypoxia, hypoglycemia and hypercapnia and enhance our knowledge concerning the role of nitric oxide in cerebral vasodilatory function.