Sympathetic Neural Control Mechanisms in Hypertension

说明(申请人提供)：拟议的研究(继续GM65958-01)寻求(I)继续开发用于神经递质释放的体外计时安培测量的钻石微电极，并用于微毛细管分离技术，结合电化学检测分析生物体液中的儿茶酚胺神经递质和代谢物，以及(Ii)将这些工具应用于研究高血压时动脉和静脉的交感神经控制机制。在美国，高血压是一个主要的健康问题。患有慢性高血压的人器官损伤和心血管疾病的风险很高。尽管风险因素是已知的，治疗方法也已被开发出来以缓解症状，但对潜在的生物学途径和机制知之甚少。我们研究计划的一个目标是更好地了解交感神经系统如何影响高血压的发展和维持，以及慢性高血压对心血管系统功能和抵抗力的影响。研究的具体目标包括以下几个方面。具体目的1：交感神经对动脉和静脉的控制存在差异。这些差异包括释放的神经递质、控制释放的受体和机制，以及神经递质活动的终止。我们试图了解这些过程在高血压中是如何改变的。特定目的2：DOCA-盐性高血压大鼠血浆内皮素-1活性升高。已知这些动物的交感神经活性升高，ET-1可能参与了高血压交感神经功能的改变。我们试图了解ET-1活性的机制，以及它是如何调节交感神经释放NE的。我们还试图了解ET-1是否可以调节供应肠系膜动脉的交感神经的ATP释放，以及这种反应是否在高血压时发生改变。

DESCRIPTION (provided by applicant): The proposed research (continuation of GM65958-01) seeks (i) to continue development of the diamond microelectrode for in vitro chronoamperometric measurements of neurotransmitter release and for use in microcapillary separation techniques coupled with electrochemical detection for the analysis of catecholamine neurotransmitters and metabolites in biological fluids, and (ii) to apply these tools to the study of sympathetic neural control mechanisms of arteries and veins in hypertension. Hypertension is a major health problem in the U.S. Those suffering from chronic high blood pressure are at high risk for organ damage and cardiovascular disease. Although the risk factors are known and treatments have been developed to alleviate symptoms, little is known about the underlying biological pathways and mechanisms. A goal of our research program is to gain a better understanding of how the sympathetic nervous system influences the development and maintenance of hypertension, and what effect chronic hypertension has on the cardiovascular system function and resistance to disease. Specific aims for the research include the following. Specific Aim 1: There are differences between sympathetic neural control of arteries and veins. These differences include the neurotransmitters released, receptors and mechanisms controlling release, and termination of the actions of the neurotransmitters. We seek to understand how these processes are altered in hypertension. Specific Aim 2: Endothelin-1 (ET-1) activity is increased in DOCA-salt hypertensive rats. It is also known that sympathetic activity is elevated in these animals and that ET-1 may be involved in changing sympathetic function in hypertension. We seek to understand the mechanism of ET-1 activity and how it can modulate NE release from sympathetic nerves. We also seek to understand if ET-1 can modulate ATP release from sympathetic nerves supplying mesenteric arteries and if this response is altered in hypertension.