NEURONAL CALCIUM CURRENT ALTERATIONS IN HYPERTENSION

高血压中神经元钙电流的变化

基本信息

批准号：
2220952
负责人：
Stephen R Ikeda
金额：
$ 10.44万
依托单位：
AUGUSTA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1989
资助国家：
美国
起止时间：
1989-07-01 至 1994-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/2220952
关键词：
animal age group biophysics calcium channel catecholamine inhibitor disease /disorder model electrophysiology ganglions genetic strain neurogenic hypertension neurons neurotransmitters pathology spontaneous hypertensive rat sympathetic nervous system

项目摘要

The aim of the proposed research is to further our understanding of the role of the sympathetic neuron calcium current in the pathogenesis and maintenance of hypertension. Recent studies have shown that an exaggerated release of norepinephrine (NE) from peripheral adrenergic nerve terminals may e one of the mechanisms producing hypertension in the spontaneously hypertensive rat (SHR) model of primary hypertensin. Although the mechanism underlying this phenomenon remains obscure, it has been proposed that a dysfunction in the presynaptic receptor mediated regulation of calcium-dependent exocytotic NE release may be responsible. Thus, the hypotheses to be tested are that: 1) an alteration in the biophysical properties and/or 2) an alteration in the neurotransmitter modulation, of the sympathetic ganglion voltage-gated calcium current is associated with the development and/or maintenance of hypertension in SHR. Accordingly, the Specific Aims of the proposal are to compare the properties ad neurotransmitter modulation of the voltage-gated calcium current of superior cervical ganglion (SCG) neurons acutely isolated from SHR and age-matched normotensive Wistar-Kyoto (WKY) rats. This will be accomplished using the patch-clamp technique in the whole-cell voltage- clamp mode. The following calcium current processes will be studied: 1) biophysical properties, i.e. activation, dihyrodopyridine sensitivity, and current density; and 2) the effect of and concentration-response relationship for NE and adenosine, agents which inhibit NE release, and isoproterenol and angiotensin II, agents which stimulate NE release. These studies will be done on both young SGR (4-6 weeks) in the "prehypertensive phase" ad older SHR (20-24 weeks) in the "established phase" of hypertension to explore the relationship between development of hypertensin and calcium current properties. In addition, studies will be performed to determine whether calcium current alterations are specific to the genetic SHR model of hypertensin. Although there is considerable evidence suggesting a role for the peripheral sympathetic nervous system in the pathogenesis and maintenance of hypertension in SHR, the electrophysiology of sympathetic ganglion neurons in SHR has received little attention. It is hoped that the proposed study will help fill this void in our understanding of the pathobiology of hypertension and provide a basis for the development of improved antihypertensive agents.

拟议研究的目的是进一步了解我们对交感神经元钙电流在发病机理和维持高血压。最近的研究表明夸张的肾上腺素（NE）从外周肾上腺神经末端可能会在该机制中产生高血压的一种机制原发性高血压素的自发性高血压大鼠（SHR）模型。尽管这种现象的基础机制仍然晦涩难懂，但它具有被提出，突触前受体介导的功能障碍钙依赖性胞吐NE释放的调节可能是造成的。因此，要测试的假设是：1）生物物理特性和/或2）神经递质的改变调节，交感神经节电压门控钙电流为与高血压的发展和/或维持 shr。因此，该提案的具体目的是比较特性AD神经递质的电压门控钙调制上颈神经节（SCG）神经元的电流急性分离 SHR和年龄匹配的正常的Wistar-Kyoto（WKY）大鼠。这将是在整个细胞电压中使用贴片钳技术完成了夹具模式。将研究以下钙电流过程：1）生物物理特性，即激活，二吡啶吡啶敏感性，和电流密度； 2）浓度响应的效果 NE和腺苷的关系，抑制NE释放的药物，以及异丙肾上腺素和血管紧张素II，刺激NE释放的药物。这些研究将在两个年轻的SGR（4-6周）中进行 “建立的” 探索高血压的阶段催眠蛋白和钙电流特性。此外，研究将是执行以确定钙电流的变化是否特定到催眠蛋白的遗传SHR模型。尽管有大量证据表明发病机理中的外周交感神经系统 SHR中的高血压，交感神经的电生理学 SHR中的神经元很少受到关注。希望拟议的研究将有助于填补我们对高血压病理生物学，并为发展提供了基础改善了降压药。