Cardiovascular Response to Glutamate Nitric Oxide

心血管对谷氨酸一氧化氮的反应

• 批准号: 6897284
• 负责人: William Temple Talman
• 金额: $ 22.05万
• 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 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6897284
• 关键词: baroreceptors; biological signal transduction; cardiovascular function; confocal scanning microscopy; cyclic GMP; electron microscopy; free radical scavengers; glutamate receptor; glutamates; guanylate cyclase; immunocytochemistry; laboratory rat; microinjections; neural transmission; neurochemistry; neuroregulation; nitric oxide; nitric oxide synthase; solitary tract nucleus

DESCRIPTION (provided by applicant): We have localized immunoreactivity for neuronal nitric oxide synthase, glutamate, NMDAR1 receptor subunits, and GLUR1 receptor subunits in the nucleus tractus solitarii (NTS) of rats and have identified strong associations between glutamate and nNOS and between each of the receptor types and nNOS in NTS. Our pharmacological studies suggest that responses to activation of glutamate receptors in NTS represent integrated action dependent on a link between ionotropic glutamate receptor and nitric oxide mechanisms in the NTS. The current protocols utilize immunohistochemical light, confocal and electron microscopic techniques and pharmacological methods to test the hypothesis that baroreflex transmission through ionotropic glutamate receptors in the nucleus tractus solitarii depends on neuronal nitric oxide synthase and soluble guanylate cyclase. There are two multifaceted specific aims. First we seek to define physiological and anatomical relationships between glutamatergic baroreceptor transmission and nNOS in NTS. Second, we seek to define physiological and anatomical relationships between glutamate receptors and cyclic GMP in NTS. We anticipate these studies will demonstrate that cardiovascular responses elicited by activation of NMDA and non-NMDA ionotropic glutamate receptors in NTS will depend to a significant degree on an intact nitroxidergic system in NTS, that responses will be attenuated or lost with interruption of the latter system, and that baroreflexes will be attenuated by interruption of nitric oxide synthesis or transduction of nitric oxide signals through soluble guanylate cyclase. We anticipate that our anatomical studies will show, at the electron micrsocopic level, that ionotropic glutamate receptors are frequently associated with nNOS and soluble guanylate cyclase immunoreactivity. Metabotropic receptors may be similarly associated, but at the electron microscopic level we expect to find that the latter receptors lie presynaptically with respect to nNOS neurons while the former predominantly occur postsynaptically, i.e. on nNOS immunoreactive dendrites or neurons in NTS.

描述(申请人提供)：我们在大鼠孤束核(NTS)内定位了神经元型一氧化氮合酶、谷氨酸、NMDAR1受体亚基和GLUR1受体亚基的免疫反应，并发现谷氨酸与nNOS以及每种受体类型与NTS中的nNOS之间存在强烈的联系。我们的药理学研究表明，NTS对谷氨酸受体激活的反应是依赖于NTS中离子型谷氨酸受体和一氧化氮机制之间的联系的综合作用。目前的方案利用免疫组织化学、共聚焦和电子显微镜技术以及药理学方法来验证孤束核内压力感受性谷氨酸受体的压力感受性传递依赖于神经元性一氧化氮合酶和可溶性鸟氨酸环化酶的假说。有两个多方面的具体目标。首先，我们试图确定孤束核内谷氨酸能压力感受器传递和nNOS之间的生理和解剖学关系。其次，我们试图确定NTS中谷氨酸受体和环状GMP之间的生理和解剖学关系。我们预计这些研究将证明，NTS中NMDA和非NMDA型离子亲电谷氨酸受体的激活引起的心血管反应将在很大程度上依赖于NTS中完整的氮氧化物能系统，该反应将随着后者系统的中断而减弱或消失，压力反射将通过中断一氧化氮合成或通过可溶性鸟苷环化酶转导一氧化氮信号而减弱。我们预计，我们的解剖学研究将在电子显微镜水平上表明，离子型谷氨酸受体经常与nNOS和可溶性鸟苷环化酶免疫反应有关。代谢性受体可能有类似的联系，但在电子显微镜水平上，我们希望发现后者位于nNOS神经元的突触前，而前者主要发生在突触后，即NTS内的nNOS免疫反应阳性树突或神经元上。