PREVENTION OF STROKE AND KIDNEY DYSFUNCTION BY ACE

这是一项研究肾素-血管紧张素系统作用的建议。 (RAS)在卒中肾血管疾病和卒中发病机制中的作用 易感自发性高血压大鼠(SHRSP)。该提案的基础是 我们最近的工作表明，用西沙必利治疗饮用盐水的SHRSP 血管紧张素转换酶抑制剂(依那普利、卡托普利和赛那普利)或Ang II 受体拮抗剂DUP 753预防肾血管病变 疾病和中风，对血压影响很小或没有影响。 重要的是，血管紧张素转换酶抑制剂的肾血管保护作用 慢性应用血管紧张素转换酶II可逆转饮用生理盐水的SHRSP。 因此，血管紧张素转换酶抑制剂和DUP 753的血管保护作用 可归因于抑制合成或阻断 血管紧张素Ⅱ的血管毒性作用这一结论暗示血管紧张素Ⅱ 在血管病变的发展过程中起着病理生理学作用 在SHRSP中伴随着食盐喂养。该项目的目的是确定 与RAS变化相关的一系列事件与 高血压、蛋白尿、血管通透性、肾功能和 血管损伤。血管病变的时程和器官特异性 通透性变化作为血管损伤的早期标志将是 在SHRSP和WKY中测定了正常和高盐摄入量。影响 血管紧张素转换酶抑制剂或血管紧张素Ⅱ受体拮抗剂治疗的时程 血管通透性变化的器官特异性将被确定。 更改租援计划的时间表将会厘定，并 与高血压、蛋白尿、肾损害的关系 功能障碍、血管通透性和血管损伤。无论是 血管紧张素转换酶抑制剂治疗能够影响这些变化是由于 将审查血管紧张素II水平的减少。我们还将确定 无论是血管紧张素转换酶II，全身输液还是直接给药 微灌入大脑皮层，可起到逆转保护作用 血管紧张素转换酶抑制剂治疗盐水型自发性高血压综合征的疗效观察 与喝盐水的WKY相比，反应性。我们的研究将提供 与血管紧张素转换酶II和血管发病机制相关的重要信息 疾病。

This is a proposal to investigate the role of the renin-angiotensin system (RAS) in the pathogenesis of renal vascular disease and stroke in stroke- prone spontaneously hypertensive rats (SHRSP). The proposal is based on our recent work demonstrating that treatment of saline-drinking SHRSP with either ACE inhibitors (enalapril, captopril, and ceranopril) or an ANG II receptor antagonist, Dup 753, results in prevention of renal vascular disease and stroke with minimal or no effect on blood pressure. Importantly, the renal vascular protective effect of ACE inhibitors in saline-drinking SHRSP could be reversed by chronic infusion of ANG II. Accordingly, the vascular protective effect of ACE inhibitors and DuP 753 is attributable to inhibition of the synthesis or blockade of the vasculotoxic actions of ANG II. Implied in this conclusion is that ANG II plays a pathophysiologic role in the development of vascular lesions that accompany salt feeding in SHRSP. The aim of this project is to determine the sequence of events relating changes in the RAS to the development of hypertension, albuminuria, vascular permeability, renal function and vascular lesions. The time-course and organ specificity for vascular permeability changes as an early marker for vascular damage will be determined in SHRSP and WKY on normal- and high-salt intake. The influence of ACE inhibitor or ANG II receptor antagonist treatment on the time-course and organ specificity for vascular permeability changes will be determined. The time-course for alterations in the RAS will be determined and correlated with the development of hypertension, albuminuria, renal dysfunction, vascular permeability and vascular lesions. Whether the ability of ACE inhibitor treatment to affect these changes is due to reductions in ANG II levels will be examined. We will also determine whether ANG II administration, either by systemic infusion or direct microperfusion into brain cerebral cortex, can reverse the protective effects of ACE inhibitor therapy in saline-drinking SHRSP and the responsiveness compared with saline-drinking WKY. Our studies will provide important information relevant to ANG II and the pathogenesis of vascular disease.