NO AND THE MAGNOCELLULAR NEUROENDOCRINE SYSTEM

NO 与大细胞神经内分泌系统

• 批准号: 6091898
• 负责人: MASSAKO KADEKARO-KUTYNA
• 金额: $ 24.38万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-04-01 至 2003-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6091898
• 关键词: angiotensin II; body fluid osmolarity; cyclic GMP; diaminoacid; enzyme activity; enzyme inhibitors; guanylate cyclase; hormone regulation /control mechanism; laboratory rat; neuroendocrine system; nitric oxide; nitric oxide synthase; oxytocin; prostaglandins; supraoptic nucleus

DESCRIPTION: (Adapted from the Investigator's Abstract) The investigators have shown previously that nitric oxide (NO), a lipophilic gas synthesized by NO synthase (NOS) from L-arginine, has important functions in neuroendocrine and behavioral osmoregulation, as well as blood pressure control. The experiments proposed in this application will clarify the site and mechanisms by which NO modulates the magnocellular neuroendocrine system. Since NO is synthesized in magnocellular neurons and cells in the supraoptic nuclei (SON) project almost exclusively to the posterior lobe of the pituitary gland to regulate neuroendocrine responses to fluid and electrolyte imbalances our studies will focus on the SON. The studies are designed to test two hypotheses: 1) NO synthesized locally in the SON during osmotic stimulation activates guanylyl cyclase to increase 3',5' cyclic guanosine monophosphate (cGMP) which results in 2) inhibition of angiotensin II and prostaglandin release in the SON to attenuate peripheral secretion of oxytocin. The specific aims are to determine: 1a) whether the activities of NOS (i.e. citrulline) and guanylyl cyclase (i.e. cGMP) increase in microdialysates of the SON during osmotic stimulation; 1b) whether inhibiting the production of NO with L-Name retrodialyzed in both SON prevents the increase of cGMP in microdialysates associated with increasing plasma levels of oxytocin during osmotic stimulation; 1c) whether retrodialyzing both SON with 1H-[1,2,4) oxodiazolo [4,3-a)quinoxalin-1-one (ODQ), a specific inhibitor of soluble guanylyl cyclase, decreases intranuclear production of cGMP and reproduces the effects of L-Name on plasma secretion of oxytocin during osmotic stimulation. 2a) whether ANG II and prostaglandin levels increase locally in the SON following retrodialysis with L-NAME during osmotic stimulation; 2b1) whether this neuroendocrine response to L-NAME can be prevented by losartan, an ANG II AT1 subtype receptor antagonist, or 2b2) indomethacin, an inhibitor of cyclooxygenase, the enzyme that converts arachidonic acid to prostaglandins. This research is important because it will further our understanding of the neurobiology of body fluid regulation by NO. Since NO is required for plasticity of neural systems involved in learning and memory, as well as participates in neurotoxicity, clarifying the mechanisms of action of this novel neurotransmitter may lead to new drug therapies selective for treatment of pathological disorders affecting water balance with minimal effect on other physiological responses.

描述：（根据调查员的摘要进行了改编） 研究人员先前已经表明，一氧化氮（NO），一种亲脂性 L-精氨酸的无合酶（NOS）合成的气体具有重要功能 在神经内分泌和行为渗透压以及血压中 控制。本应用程序中提出的实验将阐明该站点，并 没有调节大细胞神经内分泌系统的机制。自从 NO在上核中的大细胞神经元和细胞中合成 （儿子）几乎完全向垂体的后叶进行项目 调节神经内分泌对流体和电解质失衡的反应 研究将重点放在儿子上。研究旨在检验两个假设： 1）在渗透刺激激活过程中，在儿子中没有局部合成 Guanylyl环化酶增加3'，5'环鸟嘌呤一磷酸（CGMP） 结果2）SON中抑制血管紧张素II和前列腺素释放 减弱催产素的外周分泌。 具体目的是确定：1​​A）NOS的活动是否（即 瓜氨酸）和瓜尼环酶（即CGMP）增加的微轴承 儿子在渗透刺激中； 1b）是否抑制NO的产生 在两个儿子中l-名改造的l-名称可防止CGMP的增加 与血浆水平升高的催产素相关的微晶状体 渗透刺激； 1C）是否会用1H-逆转儿子[1,2,4） Oxodiazolo [4,3-A）Quinoxalin-1-One（ODQ），一种特异性抑制剂 Guanylyl环化酶减少CGMP的核内产生并再现 L-名称对渗透刺激过程中催产素分泌的影响。 2A）ANG II和前列腺素水平是否在儿子中局部增加 在渗透刺激期间带有L-名称的转化透析后； 2b1）是否 Ang II的Losartan可以预防这种神经内分泌对L名称的反应 AT1亚型受体拮抗剂或2B2）吲哚美辛，一种抑制剂 环氧酶，将花生四烯酸转化为前列腺素的酶。 这项研究很重要，因为它将进一步我们对 体液调节的神经生物学。因为不需要 与学习和记忆有关的神经系统的可塑性以及 参与神经毒性，阐明该作用的机制 新型神经递质可能会导致新药物疗法选择治疗 影响水平平衡的病理障碍，对其他 生理反应。