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ANGIOTENSIN RECEPTOR FUNCTION IN THE DORSAL MEDULLA

背髓质中的血管紧张素受体功能

基本信息

批准号：
2028315
负责人：
Debra I Diz
金额：
$ 19.52万
依托单位：
WAKE FOREST UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1988
资助国家：
美国
起止时间：
1988-04-01 至 1997-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/2028315
关键词：
afferent nerve angiotensin /renin /aldosterone hypertension angiotensin II autoradiography baroreceptors chemical binding electron microscopy endocrine pharmacology hormone receptor hormone regulation /control mechanism laboratory rat medulla oblongata neuroanatomy neuronal transport neurotransmitters norepinephrine prostaglandins

项目摘要

The objectives are to extend recent findings of interactions with various transmitters (TRs) to determine whether direct or indirect actions of angiotensin peptides mediate the acute CV and baroreceptor effects. Preliminary data suggest that Ang II increases basal release of substance P (SP), but tends to reduce SP release evoked by high potassium. Moreover, others showed that Ang II causes excitation of nodose ganglion neurons, after which a partial depolarization exists. This would tend to reduce responsiveness to a subsequent stimulus. On this basis, my new hypothesis is that Ang II releases SP or norepinephrine (NE) from post- synaptic cells to mediate the acute hypotensive and bradycardic effects. However, Ang II inhibits (or does not facilitate) SP release from vagal afferent fibers when the baroreceptor reflex is activated, leading to attenuation of the baroreceptor reflex. AIM I is to complete the pharmacological profile of the Ang II binding sites in the DMM by determining the Ang receptor subtype(s) mediating release of SP, NE and prostaglandins (PGs) from DMM slices using subtype selective antagonists. These studies are based on our finding of a topographic distribution of DMM receptors with differential sensitivity to AT1 and AT2 competitors. AIM II is to determine whether dose-related CV effects of Ang peptides are linked to release of SP, NE or PGs. Localized injections of relatively specific neurotoxins and pharmacologic antagonists for the above TRs, and synaptic blockade will be used to assess whether the blockade will alter the acute CV responses to microinjections of Ang peptides in the DMM. While the acute CV effects of Ang peptides in the DMM appear to mimic activation of the reflex (hypotensive and bradycardic), Ang II infusions peripherally or centrally inhibit the baroreceptor reflex. Ang II and Ang-(1-7) differentially alter release of SP, NE and PGs, and have opposite effects on the reflex. Thus the opposite effects of Ang II versus Ang-(1-7) on the baroreceptor reflex are a consequence of differential effects on SP, NE, and PGs release. AIM III will determine whether blockade or depletion of the above TR systems alters modulation of the reflex resulting from the Ang peptides. Parallel microdialysis experiments before and during activation of the reflex will verify that release of the particular TRs is modulated by the Ang peptides in a manner consistent with the predicted effects on the reflex.

其目的是扩展最近的研究结果的相互作用，发射机（TR），以确定是否直接或间接的行动，血管紧张素肽介导急性CV和压力感受器效应。初步数据表明，血管紧张素II增加物质的基础释放， P（SP），但倾向于减少高钾引起的SP释放。此外，其他研究表明Ang II会引起结状神经节兴奋神经元，之后存在部分去极化。这将倾向以降低对后续刺激的反应。在此基础上，新一种假说认为，血管紧张素II释放SP或去甲肾上腺素（NE）后，突触细胞介导急性水肿和心动过缓效应。然而，血管紧张素II抑制（或不促进）SP从迷走神经的释放，当压力感受器反射被激活时，压力感受器反射的衰减。目标一是完成 DMM中Ang II结合位点的药理学特征，确定介导SP、NE和NE释放的Ang受体亚型，使用亚型选择性拮抗剂的DMM切片中的前列腺素（PG）。这些研究是基于我们发现的地形分布，对AT 1和AT 2竞争者具有不同敏感性的DMM受体。目的II是确定血管紧张素肽的剂量相关性CV效应是否与SP、NE或PG的释放有关。局部注射相对特异的神经毒素和药理学拮抗剂，以上TR，和突触阻滞将用于评估是否阻断将改变对微量注射Ang的急性CV反应 DMM中的肽。而Ang肽的急性CV效应在 DMM似乎模仿反射的激活（反射和反射）。心动过缓），血管紧张素II输注外周或中枢抑制压力感受器反射 Ang II和Ang-（1-7）差异性地改变血管紧张素的释放而对反射的作用则相反。因此血管紧张素II与血管紧张素-（1-7）对压力感受性反射的相反作用是对SP、NE和PGs释放的不同影响的结果。 AIM III将确定是否阻断或耗尽上述TR 系统改变由Ang肽引起的反射的调节。在活化前和活化过程中进行平行的微透析实验，反射将验证特定TR的释放是由血管紧张素肽以与预测的对血管紧张素受体的作用一致的方式表达。反射。