CAPTOPRIL AND ANGIOTENSIN VASCULAR EFFECTS IN SENESCENCE

循环系统的动态平衡控制受损导致 病态和致命性心血管事件的高发生率困扰着 老年人。肾素-血管紧张素系统(RAS)的时间生物学变化 因此，它可能代表着重要的病理生理改变 老化的过程。许多研究都记录了与年龄相关的 血浆肾素活性(PRA)和血浆醛固酮的降低 集中精神。基于这些数据，许多研究人员考虑了RAS 在衰老过程中活性减弱，并预测血管紧张素转换 酶(ACE)抑制剂不能有效治疗高血压 在老年人口中。关于RAS活动的结论， 然而，在老年人身上的推论是很少有研究衡量的 血管紧张素II(All)，生物学上是RAS最重要的成分。 也许是由于用于测量所有人的化验方法的局限性， 不一致和矛盾的结果已经注意到关于 PRA与ALL浓度的关系。此外，ALL的血管 对特定水平的PRA的影响尚未得到很好的表征。因此， PRA仍不是反映RAS活性的可靠指标 衰老。重要的是，累积的结果来自以下几行 调查，包括证明血管紧张素转换酶持续有效的数据 在老年人中的抑制物，表明RAS继续发挥作用 在血压的动态平衡控制中起着重要作用 生活的一部分。这项提案将通过以下方式在老年人中探讨这一问题 卡托普利作用机制的阐明及血管的表征 RAS的活动。卡托普利的动力学-动力学关系将为 用灵敏和特异的方法测定药物和各种 响应参数。除了对RAS的这种操纵之外，其他 旨在改变这一系统的生理和药物操作将 用来研究PRA、所有浓度之间的关系 和血管反应性。PRA将通过传统方法和 真正的全部浓度将在层析后确定 从干扰代谢物中分离出来。评估血管效应 在与RAS活动的特定状态相对应的所有事件中， 局部血管对所有注入臂动脉的反应将 通过静脉闭塞体积描记术进行测量。作为比较，杨 控制对象也将被研究。这项提案的结果应该是 进一步深入了解 年龄对RAS的影响，进而可能影响治疗 针对老年人高血压等疾病的策略。

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.