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CAPTOPRIL AND ANGIOTENSIN VASCULAR EFFECTS IN SENESCENCE

卡托普利和血管紧张素对衰老的血管作用

基本信息

批准号：
3121436
负责人：
JAMES VOELKER
金额：
$ 13.73万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
1991
资助国家：
美国
起止时间：
1991-02-01 至 1994-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/3121436
关键词：
aging angiotensin /renin /aldosterone hypertension angiotensin II blood chemistry blood pressure captopril cardiovascular pharmacology hemodynamics human old age (65+) human subject norepinephrine plethysmography young adult human (21-34)

项目摘要

Impaired homeostatic control of the circulatory system contributes to the high incidence of morbid and fatal cardiovascular episodes afflicting the elderly. Chronobiologic changes in the renin-angiotensin system (RAS), therefore, may represent important pathophysiologic modifications during the aging process. A number of studies have documented age-associated reductions in plasma renin activity (PRA) and plasma aldosterone concentration. Based on these data, many investigators have considered RAS activity to diminish during aging and predicted that angiotensin converting enzyme (ACE) inhibitors would not be efficacious in treating hypertension in the geriatric population. The conclusions regarding RAS activity, however, are inferences as few studies in elderly humans have measured angiotensin II (All), biologically the most important component of the RAS. Perhaps due to limitations in the assays employed to measure All, discordant and paradoxical results have been noted regarding the relationship between PRA and All concentration. Furthermore, All's vascular effect for a particular level of PRA has not been well characterized. Thus, it has not been shown that PRA remains a reliable index of RAS activity in senescence. Importantly, the accrued results from several lines of investigation, including data demonstrating a continued efficacy of ACE inhibitors in the elderly, suggest that the RAS continues to play an important role in the homeostatic control of blood pressure throughout all of life. This proposal will explore this issue in elderly humans by elucidating captopril's mechanism of action and characterizing the vascular activity of the RAS. Captopril's kinetic-dynamic relationship will be determined employing sensitive and specific assays for the drug and various response parameters. In addition to this manipulation of the RAS, other physiologic and pharmacologic maneuvers designed to alter the system will be used in order to study the relationships between PRA, All concentration and vascular reactivity. PRA will be measured by conventional methods and the true All concentration will be determined after chromatographic separation from interfering metabolites. To evaluate the vascular effect of All that corresponds to a particular state of RAS activity, the localized vascular response to All infused into the brachial artery will be measured by venous occlusion plethysmography. For comparison, young control subjects will also be studied. Results from this proposal should provide further insights into the functional significance of the age-associated affects on the RAS which, in turn, may influence treatment strategies for diseases such as hypertension in the elderly.

循环系统的稳态控制受损有助于困扰人们的病态和致命心血管事件发生率很高老人肾素-血管紧张素系统（RAS）的时间生物学变化，因此，可能代表重要的病理生理学改变，衰老的过程许多研究都记录了与年龄相关的血浆肾素活性（PRA）和血浆醛固酮降低浓度.基于这些数据，许多研究者认为RAS 活性在衰老过程中减少，并预测血管紧张素转换酶（ACE）抑制剂治疗高血压无效在老年人群中。关于RAS活动的结论，然而，在老年人中进行的研究很少测量血管紧张素II（All），在生物学上是RAS的最重要成分。可能由于用于测量All的测定的局限性，已经注意到关于 PRA和All浓度之间的关系。此外，所有的血管特定水平PRA的效果尚未得到很好的表征。因此，在本发明中，没有证据表明PRA仍然是RAS活性的可靠指标，衰老重要的是，从几行的累积结果，研究，包括证明ACE持续疗效的数据抑制剂，表明RAS继续发挥作用，在整个血压的稳态控制的重要作用生命该提案将通过以下方式在老年人中探索这一问题：阐明了卡托普利的作用机制并表征了血管 RAS的活动。卡托普利的动力学-动力学关系将是采用药物和各种药物的敏感性和特异性测定法测定响应参数除了对RAS的这种操纵之外，其他旨在改变系统的生理和药理学操作将用于研究PRA、所有浓度之间的关系和血管反应性。PRA将通过常规方法测量，将在色谱分析后测定所有真实浓度与干扰代谢物分离。评价血管效应对应于RAS活动的特定状态的All中，对输注到肱动脉中的All的局部血管反应将通过静脉闭塞体积描记法测量。相比之下，年轻此外，亦会研究控制受试者。该提案的结果应提供进一步的见解的功能意义，年龄相关的RAS影响，反过来可能影响治疗老年人高血压等疾病的治疗策略。