CARDIOVASCULAR RESPONSE TO GLUTAMATE NITRIC OXIDE

对谷氨酸一氧化氮的心血管反应

• 批准号: 6125859
• 负责人: William Temple Talman
• 金额: $ 17.49万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-12-15 至 2002-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6125859
• 关键词: biological signal transduction; cardiovascular function; cyclic GMP; free radical scavengers; glutamates; immunocytochemistry; immunoelectron microscopy; laboratory rat; luminescence; microinjections; neural transmission; neurochemistry; neuroregulation; nitric oxide; solitary tract nucleus

The nucleus tractus solitarii (NTS) plays a critical role in cardio- vascular regulation. Glutamate (GLU) is a putative neurotransmitter in cardiovascular regions of the NTS where nitric oxide (NO) or nitrosyl factors elicit cardiovascular responses similar to those produced by GLU. Activation of GLU receptors at other central sites has been shown to cause release of NO, but studies have not been done to determine if GLU influences NO in NTS and, if so, if NO contributes to responses to GLU. Preliminary data suggest that GLU and NO containing nerves lie in close proximity in NTS and that inhibition of synthesis of NO by local neurons attenuates responses to GLU. The hypothesis of the current study is that responses to GLU in NTS are linked to NO. There are four specific aims. The first aim is to determine if NO participates in mediating cardiovascular effects produced by GLU receptor agonists in the NTS. Pharmacological studies will assess cardiovascular responses to injection of GLU agonists into the NTS of awake, unrestrained rats both before and after injection at the same site of reduced hemoglobin, a scavenger of NO; an inhibitor of neuronal NO synthase; L-arginine, the precursor of NO; or a donor of NO The second aim is to determine if NO is released from the NTS exposed to GLU receptor agonists. This in vitro neurochemical study will utilize freshly prepared tissue from NTS dissected from slices of rat brain stem and will measure NO by the chemiluminescence method. The third aim is to determine if effects of GLU on soluble guanylate cyclase are mediated through NO. An in vivo study will determine if blockade of soluble guanylate cyclase, an important step in signal transduction mediated by NO, alters responses to GLU microinjected into the NTS of awake rats. An in vitro study will directly assess effects of GLU on formation of cyclic GMP and will study the role of NO in producing those effects. The fourth aim is to determine the anatomical relationship between GLU terminals and neuronal elements that contain NO synthase (NOS) in the NTS. These studies will be important in expanding our understanding a) interrelationships between two putative transmitters in the NTS, b) the role of NO or nitrosyl factors in generating cardiovascular responses from NTS and c) cardiovascular influences of NTS in awake animals.

孤束核（NTS）在心脏功能中起着至关重要的作用。 血管调节。 谷氨酸 (GLU) 是一种假定的神经递质 NTS 的心血管区域，其中一氧化氮 (NO) 或亚硝酰基 因素引起的心血管反应类似于 谷氨酰胺。 其他中心位点 GLU 受体的激活已被证实 导致 NO 的释放，但尚未进行研究以确定是否 GLU 影响 NTS 中的 NO，如果是这样，NO 是否有助于响应 GLU。 初步数据表明，含有 GLU 和 NO 的神经位于 NTS 非常接近，局部抑制 NO 合成 神经元减弱对 GLU 的反应。当前研究的假设 NTS 中对 GLU 的反应与 NO 相关。 有四个 具体目标。 第一个目标是确定 NO 是否参与 介导 GLU 受体激动剂产生的心血管作用 NTS。药理学研究将评估心血管反应 将 GLU 激动剂注射到清醒、不受约束的大鼠的 NTS 中 在血红蛋白减少的同一部位注射之前和之后， NO 的清除剂；神经元NO合酶抑制剂； L-精氨酸， NO 的前体；或 NO 捐赠者 第二个目标是确定 NO 是否 从暴露于 GLU 受体激动剂的 NTS 中释放。 这在 体外神经化学研究将利用 NTS 新鲜制备的组织 从大鼠脑干切片上解剖并通过 化学发光法。 第三个目标是确定 可溶性鸟苷酸环化酶上的 GLU 通过 NO 介导。 体内 研究将确定是否阻断可溶性鸟苷酸环化酶 NO 介导的信号转导的重要一步，改变反应 将GLU显微注射到清醒大鼠的NTS中。 一项体外研究将 直接评估 GLU 对环 GMP 形成的影响并将研究 NO 在产生这些效应中的作用。 第四个目标是 确定 GLU 末端和神经元之间的解剖关系 NTS 中含有 NO 合酶 (NOS) 的元件。这些研究将 对于扩大我们的理解很重要 a) 相互关系 NTS 中两个假定的递质之间，b) NO 或 NTS 产生心血管反应的亚硝酰因子和 c) NTS 对清醒动物心血管的影响。