VSM CHLORIDE PERMEABILITY IN HYPERTENSION

高血压时 VSM 氯离子渗透性

• 批准号: 3364072
• 负责人: TOMMY A BROCK
• 金额: $ 2.63万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-07-01 至 1992-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3364072
• 关键词: angiotensin /renin /aldosterone hypertension; cellular pathology; chloride channels; chlorine; familial hypertension; fluorescence microscopy; homeostasis; ion transport; laboratory rat; membrane transport proteins; molecular pathology; vascular smooth muscle; vasospasm; voltage /patch clamp

Hypertension is a major risk factor for the development of cardiovascular disease, i.e., stroke heart failure and peripheral vascular disease. Arteries from animals with genetic and mineralocorticoid-NaCl hypertension are known to exhibit increases in steady-state Cl- turnover and vasoconstrictor responsiveness. The relationship between Cl- and vascular contraction has not been clearly defined. The proposed research program focuses on the cellular/molecular mechanisms underlying altered Cl- permeability and its contribution to increased vascular reactivity in hypertension. The overall plan is designed to probe the physiological role of specific Cl- transporters/channels in modulating transmembrane signaling events (Ca2+, pHi, membrane potential) involved in contractile agonist stimulation of vascular smooth muscle cells (VSMC) isolated from arteries (aorta, caudal artery) of normotensive, spontaneously hypertensive (NaCl- sensitive and resistant strains), and aldosterone-NaCl hypertension. Combination of fluorescence microscopy, newly-developed digital imaging methods, and patch-clamp techniques will be used to probe the molecular mechanisms of VSMC Cl- homeostasis. The specific aims are: 1) Define the cellular pathways involved in Cl- homeostasis in cultured, as well as freshly isolated VSMC. Ion-selective fluorescent dyes, fluorescence microcopy, and patch-clamp techniques will be used to analyze in detail different Cl- transporters/channels in intact, single VSMC; 2) Determine the molecular mechanisms involved in Cl- transporter/channel activation. Fluorescence microscopy in combination with digital image analysis methods and patch-clamp techniques will be used to make simultaneous spatial/temporal measurements of Cl- conductances and different ions following agonists stimulation; 3) Probe the cellular/molecular mechanisms underlying increased VSMC Cl- permeability and its contribution to increase VSMC reactivity. Furthermore, we will evaluate the contribution of increased Cl- permeability to enhanced vascular responsiveness in aorta and caudal artery using different Cl- flux inhibitors. These studies will contribute to our basic understanding of the cellular/molecular mechanisms underlying normal and altered VSMC ion permeability in relationship to VSMC dysfunction in the pathogenesis of hypertension, atherosclerosis and arterial vasospasm.

高血压是心血管疾病发展的主要危险因素， 疾病，即，中风、心力衰竭和外周血管疾病。 遗传性高血压和盐皮质激素-氯化钠高血压动物的动脉 已知在稳态Cl-周转中表现出增加， 血管收缩反应性。 氯离子与血管生成的关系 收缩没有明确定义。 拟议的研究计划 关注改变Cl-的细胞/分子机制， 渗透性及其对血管反应性增加的贡献 高血压 总体计划旨在探索生理作用 特异性Cl-转运蛋白/通道在调节跨膜信号传导中的作用 收缩激动剂参与的事件（Ca2+、pHi、膜电位） 从动脉分离的血管平滑肌细胞（VSMC）的刺激 （主动脉，尾动脉）血压正常，自发性高血压（NaCl- 敏感和耐药菌株）和醛固酮-NaCl高血压。 结合荧光显微镜，新开发的数字成像 方法和膜片钳技术将用于探测分子 VSMC Cl-稳态的机制。 具体目标是：1）确定参与Cl-的细胞通路 在培养的以及新鲜分离的VSMC中的稳态。 离子选择 荧光染料、荧光显微镜和膜片钳技术将 可用于详细分析不同的Cl-转运蛋白/通道， 单个VSMC; 2）确定Cl-参与的分子机制 转运蛋白/通道激活。 荧光显微镜结合 将采用数字图像分析方法和膜片钳技术 同时进行Cl-电导的空间/时间测量， 激动剂刺激后的不同离子; 3）探测 VSMC Cl-通透性增加的细胞/分子机制 以及其对增加VSMC反应性的贡献。 此外，我们将 评估增加的Cl-渗透性对增强的 用不同氯离子流量测定主动脉和尾动脉血管反应性 抑制剂的 这些研究将有助于我们对 正常和改变的VSMC离子的细胞/分子机制 血管内皮细胞通透性与血管平滑肌细胞功能障碍的关系 高血压、动脉粥样硬化和动脉血管痉挛。