PREVENTION OF STROKE DYSFUNCTION BY ACE INHIBITION

这是一个建议，调查的作用，醛固酮及其 与钾、血管紧张素II和活性氧的相互作用 (ROS)在中风易感者的血管病理学发展中 自发性高血压大鼠（SHRSP）。 我们先前已经 确定了肾素-血管紧张素系统作为发挥核心作用， 肾和脑血管病变的发展， 动物对血压的影响无关。 当前 我们的建议是基于我们的观察，即长期服用 盐皮质激素受体拮抗剂可显著延迟 中风和恶性肾硬化的发展， 饮用SHRSP对血压的影响很小，如果有的话。 我们 最近发现活性氧的清除剂可以延长生命 在这些动物中， ACE抑制和醛固酮输注。的免疫染色 硝酸酪氨酸在饮用盐水的SHRSP中显著升高 与WKY和主动脉超氧阴离子形成相比， SHRSP减少慢性卡托普利治疗。 的 拟议的研究将集中在ROS作为介质的损害 制作。我们还将研究 盐皮质激素和氯化钾摄入量增加。 的 后者可刺激醛固酮释放， 高钠摄入可抑制SHRSP的病变产生，但可增强 正常钠摄入量下SHRSP损伤形成。 研究将 进行检查ROS对血管的贡献， 醛固酮和血管紧张素Ⅱ对自发性高血压大鼠脑损伤影响 和WKY的条件下，其中可检测的循环 醛固酮水平不存在。 我们还将研究 药理学手段来中断 肾素-血管紧张素-醛固酮对ROS生成和血管生成的影响 SHRSP中的损伤发展以及 醛固酮或血管紧张素II。 所获得的信息应确定 醛固酮在血管损伤中的作用 饮用盐水的SHRSP，并提供新的见解，血管 影响肾素-血管紧张素的药物的保护作用 系统

This is a proposal to investigate the role of aldosterone and its interactions with potassium, Ang II and reactive oxygen species (ROS) in the development of vascular pathology in stroke-prone spontaneously hypertensive rats (SHRSP). We have previously identified the renin-angiotensin system as playing a central role in the development of renal and cerebrovascular lesions in these animals independent of effects on blood pressure. The current proposal is based on our observation that chronic administration of mineralocorticoid receptor antagonists can markedly delay the development of stroke and malignant nephrosclerosis in saline- drinking SHRSP with little, if any, effect on blood pressure. We have recently found that scavengers of ROS will prolong survival in these animals and will reduce proteinuria under conditions of ACE inhibition and aldosterone infusion. Immunostaining for nitrotyrosine was markedly elevated in saline-drinking SHRSP compared with WKY and aortic superoxide anion formation in SHRSP was diminished by chronic captopril treatment. The proposed studies will focus on ROS as mediators of the damage produced. We will also examine the interrelationship between mineralocorticoids and increased potassium chloride intake. The latter can stimulate aldosterone release and reduce vascular lesion production in SHRSP on high-sodium intake, but enhances lesion formation in SHRSP on normal-sodium intake. Studies will be performed to examine the contribution of ROS to vascular lesion development in response to aldosterone and Ang II in SHRSP and WKY under conditions in which detectable circulating aldosterone levels are absent. We will also examine the effect of pharmacological means to interrupt the renin-angiotensin-aldosterone on ROS formation and vascular lesion development in SHRSP and the reversal of the effects by aldosterone or Ang II. The information obtained should define the role of aldosterone in the development of vascular injury in saline-drinking SHRSP and provide new insight into the vascular protective effects of agents affecting the renin-angiotensin system.