CAROTID BODY EXCITATION--NEW CONCEPT

颈动脉体兴奋--新概念

• 批准号: 6390135
• 负责人: MACHIKO SHIRAHATA
• 金额: $ 24.13万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-07-05 至 2003-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6390135
• 关键词: calcium channel; calcium flux; carotid body; cats; cellular polarity; chemoreceptors; hypoxia; immunocytochemistry; neurotransmitter transport; nicotinic receptors; oxygen; potassium channel; receptor sensitivity; tissue /cell culture; voltage /patch clamp; voltage gated channel

DESCRIPTION (Applicant's abstract): The carotid body is a major chemoreceptor organ whose excitation causes reflex responses in cardiopulmonary, renal and endocrine systems. Although the mechanisms of carotid body excitation are not yet clear, essential steps include the depolarization of chemosensitive glomus cells, the increase in glomus cell intracellular calcium and the release of neurotransmitters. Many studies point to the involvement of oxygen-sensitive potassium channels, but a causal relationship between the inhibition of these channels and the depolarization of glomus cells during hypoxia has not yet been established. Since cat glomus cells release acetylcholine even under normoxic/normocapnic conditions, we hypothesize that hypoxia augments the activity of neuronal nicotinic acetylcholine receptors and/or enhances the sensitivity of acetylcholine receptors for acetylcholine. This initiates the depolarization of glomus cells and the increase in intracellular calcium. Oxygen-sensitive potassium channels and voltage-gated calcium channels participate in the later phase of the changes. Preliminary data have shown that: 1) cat glomus cells expressed alpha-4 subunit containing nicotinic acetylcholine receptors, 2) acetylcholine-induced inward current and carotid body neural output were enhanced by a mild decrease in oxygen tension from normoxic levels, 3) acetylcholine increased calcium of carotid body cells, 4) oxygen-sensitive potassium current was linearly inhibited by decreasing oxygen, and 5) increased carotid body neural output in hypoxia was inhibited by L-type voltage gated calcium channels. Specific aims are to investigate: 1) the role of acetylcholine and nicotinic acetylcholine receptors for initiating the depolarization of glomus cells and the increase in calcium, 2) the contribution of oxygen sensitive potassium channels in the late phase of glomus cell depolarization during hypoxia, 3) the contribution of voltage gated calcium channels to the late phase of the calcium increase in glomus cells during hypoxia. Patch clamp, microfluorometric, and immunocytochemical techniques are to be used. This innovative proposal will advance the understanding of the excitation mechanisms of glomus cells. Once the chemotransductive mechanisms are understood, pharmacological or genetic tools can be developed to alter the carotid body function to levels desirable for treating carotid body related pathological conditions such as sudden infant death syndrome and hemodynamic changes in sleep apnea patients.

描述(申请人摘要)：颈动脉小体是一种主要的化学感受器 兴奋引起心肺、肾和心脏反射反应的器官 内分泌系统。尽管颈动脉小体兴奋的机制不是 然而，明确的、基本的步骤包括对化疗敏感的球体去极化 细胞内，球体细胞内钙的增加和细胞内钙的释放 神经递质。许多研究指出，氧敏感参与了 钾通道，但这些通道的抑制之间存在因果关系 缺氧时血管球体细胞的去极化和通道尚未被研究 已经成立了。由于猫球体细胞即使在 常氧/常压条件下，我们假设低氧增加了 神经元烟碱型乙酰胆碱受体的活性和/或增强 乙酰胆碱受体对乙酰胆碱的敏感性。这将启动 球体细胞的去极化和细胞内钙的增加。 氧敏感钾通道和电压门控钙通道 参与更改的后期阶段。初步数据显示 即：1)猫肾球瘤细胞表达含有烟碱的α-4亚单位 乙酰胆碱受体，2)乙酰胆碱诱导的内向电流和颈动脉 身体神经输出通过氧分压的轻微下降而增强 常氧水平，3)乙酰胆碱增加颈动脉体细胞钙，4) 氧敏感钾电流受氧降低呈线性抑制， (5)L抑制缺氧时颈动脉体神经输出的增加 电压门控钙通道。具体目的是调查：1)角色 乙酰胆碱和烟碱型乙酰胆碱受体启动 球体细胞的去极化和钙的增加，2)贡献 血管球体细胞晚期氧敏感钾通道的研究 低氧时的去极化；3)电压门控性钙的作用 肾小球细胞钙离子增加的晚期通道 缺氧。膜片钳、显微荧光和免疫细胞化学技术 以供使用。这一创新的建议将促进对 球体细胞的兴奋机制。一旦化学转导机制 了解到，可以开发药理或遗传工具来改变 颈动脉体部功能达到治疗颈动脉体部相关的理想水平 婴儿猝死综合征和血流动力学等病理情况 睡眠呼吸暂停患者的变化。