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)在肾血管疾病和中风的发病机制中- 自发性高血压大鼠（SHRSP）。 所涉提议主要是 我们最近的研究表明，用 ACE抑制剂（依那普利、卡托普利和西那普利）或ANG II 受体拮抗剂Dup 753可预防肾血管病变， 疾病和中风，对血压影响极小或没有影响。 重要的是，ACE抑制剂对肾血管的保护作用， 慢性输注ANG Ⅱ可逆转SHRSP。 因此，ACE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ANG II 在血管病变的发展中起病理生理作用， 伴随SHRSP的盐饲。 本项目的目的是确定 将RAS中的变化与以下发展相关的事件序列： 高血压、蛋白尿、血管通透性、肾功能和 血管病变 血管性高血压的时程和器官特异性 渗透性变化作为血管损伤的早期标志， 在SHRSP和WKY中测定正常和高盐摄入量。 的影响 ACE抑制剂或ANG II受体拮抗剂治疗的时间进程 并确定血管通透性变化的器官特异性。 将确定调整收入调整制度的时间进程， 与高血压、蛋白尿、肾性高血压的发展相关 功能障碍、血管通透性和血管病变。 是否 ACE抑制剂治疗影响这些变化的能力是由于 将研究降低ANG II水平的问题。 我们还将确定 无论是通过全身输注还是直接给予ANG II， 微灌注进入大脑皮层，可逆转保护性 血管紧张素转换酶抑制剂治疗对高血压性高血压大鼠的影响 反应性与盐水饮用WKY相比。 我们的研究将提供 血管紧张素Ⅱ和血管紧张素Ⅱ发病机制的重要信息 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.