Neurotransmission to arteries and veins in hypertension

这一主题的主题是肠系膜动脉(MA)和静脉(MV)的不同控制。 通过交感神经。我们将详细地确定这些差异，我们还将确定分子 醋酸脱氧皮质酮(DOCA)-盐性高血压相关改变的机制 大鼠交感神经向MA和MV的传递。《特定目标1》将检验这样一种假设 向MA和MV的传播是不同的，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 交感神经供应MA的三磷酸腺苷在体外释放引起的电位(EBP)。我们证明了 氧化应激是高血压患者嘌呤能信号转导MA受损的原因之一。我们还将使用 连续安培法和快速扫描循环伏安法(FSCV)用于电化学测量 交感神经与MA和MV相关的神经递质释放谱。最后，这些 研究将使用FSCV研究肾上腺嗜铬细胞释放神经递质的情况 文化。这一目的的研究将表明，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-盐性高血压中发生改变。肾上腺嗜铬细胞将作为动脉周围的模型 交感神经。《特定目标2》将检验B2-肾上腺素能受体(AR)介导的假设 DOCA-SALT大鼠的血管扩张功能减弱。我们认为DOCA-SALT中血管张力增加 高血压的部分原因是B2-AR-cAMP-蛋白激酶A信号之间的联系受损 在MA和MV中，钙通道和大电导钙激活K[](BK)通道。这些研究将 测量：B2-AR激动剂在体外引起的MA和MV的松弛，膜片钳BK通道电流 方法和异源受体和离子通道的表达来研究连接B2- ARS到BK频道。具体目标3将在DOCA-SALT大鼠身上验证MV“反向重塑”的假说。 静脉内皮源性内皮素-B和A1-肾上腺素能受体激活引起的逆性重构 与基质金属蛋白酶-2和Tenascin-C激活有关的平滑肌细胞。反向 静脉重塑是静脉对容量变化引起的静脉容量减少的一种适应性反应。 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。我们还将确定具体的 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 开发治疗高血压的新方法。

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.