Neurotransmission to arteries and veins in hypertension

这一主题的主要内容是肠系膜动脉（MA）和静脉（MV）的差异控制 由交感神经引起。我们将详细鉴定这些差异，我们还将鉴定 调节醋酸脱氧皮质酮（DOCA）盐高血压相关变化的机制 大鼠交感神经对MA和MV的传递。具体目标1将测试假设， 传递到MA和MV是不同的，这些机制在高血压中发生了差异性改变。 这些研究将利用细胞内电生理技术记录嘌呤能兴奋性连接 在离体条件下，观察了由供应MA的交感神经释放ATP引起的EJPs。我们证明了 氧化应激是导致高血压中MA的嘌呤能信号传导受损的原因。我们还将使用 连续安培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研究原发性肾上腺嗜铬细胞的神经递质释放谱， 文化为此目的的研究将表明，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到MA而不是MV 在DOCA盐高血压中改变。肾上腺嗜铬细胞将被用作动脉周围的模型 交感神经具体目标2将检验B2-肾上腺素能受体（AR）介导的 DOCA-盐大鼠的血管舒张减少。我们认为DOCA盐增加血管张力 高血压部分是由于B2-AR-cAMP-蛋白激酶A信号传导之间的联系受损 在MA和MV中，Ca[2+]激活的K[+]（BK）通道和大电导Ca[2+]激活的K[+]（BK）通道。这些研究将 测量：体外B2-AR激动剂诱导的MA和MV舒张，使用膜片钳的BK通道电流 方法和异源受体和离子通道表达来研究连接B2- AR到BK频道。具体目标3将检验DOCA-盐大鼠中MV“逆转重塑”的假设。 逆转重构是由内皮素-B激活和静脉内皮细胞上α 1-肾上腺素能受体激活引起的。 平滑肌细胞与基质金属蛋白酶-2和腱生蛋白-C活化偶联。反向 重塑是静脉对由体积偏移引起的静脉体积减小的适应性反应， 高血压时循环阻力侧的电容。这些研究将提供新的 关于动脉和静脉的不同神经体液控制的信息。我们还将确定具体 高血压患者动脉和静脉神经控制的变化，这些信息将有助于 高血压的治疗方法。

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.