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：（改编自研究者的摘要） 研究人员之前已经证明，一氧化氮（NO）是一种亲脂性物质 NO合酶（NOS）从L-精氨酸合成气体，具有重要的功能 神经内分泌和行为渗透调节以及血压 控制。本申请中提出的实验将阐明地点和 NO 调节大细胞神经内分泌系统的机制。自从 NO 在大细胞神经元和视上核细胞中合成 (SON) 几乎完全投射到垂体后叶 调节神经内分泌对液体和电解质失衡的反应 研究将集中在 SON 上。这些研究旨在检验两个假设： 1) 渗透刺激期间 SON 局部合成的 NO 被激活 鸟苷酸环化酶可增加 3',5' 环磷酸鸟苷 (cGMP)， 结果 2) 抑制 SON 中血管紧张素 II 和前列腺素的释放 减弱外周催产素的分泌。 具体目标是确定： 1a) NOS 的活性（即 瓜氨酸）和鸟苷酸环化酶（即cGMP）在微透析液中增加 渗透刺激期间的SON； 1b)是否抑制NO的产生 在两个 SON 中进行 L-Name 逆透析可以防止 cGMP 的增加 微透析与催产素血浆水平升高有关 渗透刺激； 1c) 是否用 1H-[1,2,4) 逆透析两个 SON oxodiazolo [4,3-a)quinoxalin-1-one (ODQ)，一种可溶性的特异性抑制剂 鸟苷酸环化酶，减少核内 cGMP 的产生并重现 L-Name 对渗透刺激过程中血浆催产素分泌的影响。 2a) SON中ANG II和前列腺素水平是否局部升高 在渗透刺激期间用 L-NAME 进行逆透析后； 2b1) 是否 这种对 L-NAME 的神经内分泌反应可以通过氯沙坦（一种 ANG II）来预防 AT1 亚型受体拮抗剂，或 2b2) 吲哚美辛，一种抑制剂 环加氧酶，将花生四烯酸转化为前列腺素的酶。 这项研究很重要，因为它将加深我们对 NO 体液调节的神经生物学。由于需要 NO 参与学习和记忆的神经系统的可塑性，以及 参与神经毒性，阐明其作用机制 新型神经递质可能会导致新的选择性治疗药物疗法 影响水平衡的病理紊乱对其他影响最小 生理反应。