Neurotransmission to arteries and veins in hypertension

高血压中动脉和静脉的神经传递

• 批准号: 8148066
• 负责人: James J. Galligan
• 金额: $ 32.13万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-10 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8148066
• 关键词: Acetates; Adrenal Glands; Adrenal Medulla; Adrenergic Agents; Adrenergic Agonists; Adrenergic Receptor; Arteries; Biochemical; Biomechanics; Blood Circulation; Blood Vessels; Celiac ganglion; Chromaffin Cells; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Data; Deoxycorticosterone; Development; Dilator; Elasticity; Electric Capacitance; Endothelin; Endothelin B Receptor; Endothelin-1; Epinephrine; Equilibrium; Figs - dietary; Functional disorder; Gelatinase A; Hypertension; Impairment; In Vitro; Ion Channel; Link; Measurement; Measures; Mediating; Mesenteric Arteries; Methods; Modeling; Molecular; Nerve; Neurotransmitters; Norepinephrine; Oxidative Stress; Property; Rattus; Receptor Activation; Relaxation; Resistance; Role; Scanning; Side; Signal Pathway; Signal Transduction; Smooth Muscle Myocytes; Sodium Chloride; Splanchnic Circulation; Techniques; Tenascin; Testing; Up-Regulation; Vasodilation; Veins; Venous; Venous Pressure level; adrenergic; arterial remodeling; constriction; large-conductance calcium-activated potassium channels; mesenteric vein; nerve supply; neurochemistry; neuroregulation; neurotransmission; neurotransmitter release; noradrenergic; novel; patch clamp; pressure; receptor; response; transmission process; vasoconstriction

The main theme of this theme is that there is differential control of mesenteric arteries (MA) and veins (MV) by sympathetic nerves. We will identify these differences in detail and we will also identify the molecular mechanisms mediating deoxycorticosterone acetate (DOCA)-salt hypertension associated changes in sympathetic transmission to MA and MV in rats. Specific aim 1 will test the hypothesis that sympathetic transmission to MA and MV is different and these mechanisms are differentially altered in hypertension. These studies will use intracellular electrophysiological techniques to record purinergic excitatory junction potentials (EJPs) caused by ATP released from sympathetic nerves supplying MA in vitro. We show that oxidative stress is responsible for impairment of purinergic signaling to MA in hypertension. We will also use continuous amperometry and fast scan cyclic voltametry (FSCV) to make electrochemical measurements of neurotransmitter release profiles from sympathetic nerves associated with MA and MV in vitro. Finally, these studies will use FSCV to study neurotransmitter release profiles from adrenal chromaffin cells in primary culture. The studies in this aim will show that sympathetic nerves supplying MA and MV use different neurotransmitters, release and clearance mechanisms and that sympathetic transmission to MA but not MV is altered in DOCA-salt hypertension. Adrenal chromaffin cells will used as a model of periarterial sympathetic nerves. Specific aim 2 will test the hypothesis that B2-adrenergic receptor (AR)-mediated vasodilation is reduced in DOCA-salt rats. We propose that increased vascular tone in DOCA-salt hypertension is partly due to impairment of the link between the B2-AR-cAMP-protein kinase A signaling pathway and large conductance Ca[2+] activated K[+] (BK) channels in MA and MV. These studies will measure: B2-AR agonist-induced relaxations of MA and MV in vitro, BK channel currents using patch clamp methods and heterologous receptor and ion channel expression to study molecular mechanisms linking B2- ARs to BK channels. Specific aim 3 will test the hypothesis that MV "reverse remodel" in DOCA-salt rats. Reverse remodeling is caused by activation of endothelin-B and a1-adrenergic receptor activation on venous smooth muscle cells which couple to activation of matrix metalloproteinase-2 and tenascin-C. Reverse remodeling is an adaptive response of veins to the decreased venous volume caused by volume shifts from the capacitance to the resistance side of the circulation in hypertension. These studies will provide new information about differential neurohumoral control of arteries and veins. We will also identify specific changes in neural control of arteries and veins in hypertension and this information will facilitate the development of new treatments for high blood pressure.

本主题的主题是肠系膜动脉（MA）和静脉（MV）的差异控制 通过交感神经。我们将详细识别这些差异，我们还将识别分子 介导醋酸脱氧皮质酮（DOCA）-盐高血压相关变化的机制 大鼠中 MA 和 MV 的交感神经传递。具体目标 1 将检验以下假设：同情 向 MA 和 MV 的传播是不同的，并且这些机制在高血压中发生了不同的改变。 这些研究将使用细胞内电生理技术来记录嘌呤能兴奋性连接 体外供应 MA 的交感神经释放的 ATP 引起的电位（EJP）。我们表明 氧化应激导致高血压中 MA 的嘌呤能信号传导受损。我们还将使用 连续电流分析法和快速扫描循环伏安法 (FSCV) 进行电化学测量 体外与 MA 和 MV 相关的交感神经的神经递质释放曲线。最后，这些 研究将使用 FSCV 来研究原代肾上腺嗜铬细胞的神经递质释放曲线 文化。该目标的研究将表明，供应 MA 和 MV 的交感神经使用不同的 神经递质、释放和清除机制以及交感神经传递至 MA 而不是 MV DOCA-盐高血压发生改变。肾上腺嗜铬细胞将用作动脉周围的模型 交感神经。具体目标 2 将检验 B2 肾上腺素受体 (AR) 介导的假设 DOCA-盐大鼠的血管舒张作用减少。我们建议 DOCA 盐增加血管张力 高血压的部分原因是 B2-AR-cAMP-蛋白激酶 A 信号传导之间的联系受损 MA 和 MV 中的通路和大电导 Ca[2+] 激活 K[+] (BK) 通道。这些研究将 测量：B2-AR 激动剂体外诱导 MA 和 MV 松弛，使用膜片钳的 BK 通道电流 方法以及异源受体和离子通道表达来研究连接 B2- 的分子机制 AR 至 BK 频道。具体目标 3 将检验 MV 在 DOCA 盐大鼠中“逆转重塑”的假设。 逆重塑是由静脉内皮素-B 的激活和 a1-肾上腺素能受体的激活引起的 与基质金属蛋白酶-2 和腱蛋白-C 的激活偶联的平滑肌细胞。撤销 重塑是静脉对因容量变化而导致的静脉容量减少的适应性反应 高血压时循环阻力侧的电容。这些研究将提供新的 有关动脉和静脉的神经体液差异控制的信息。我们还将确定具体 高血压患者动脉和静脉的神经控制发生变化，这些信息将有助于 开发高血压新疗法。