PREVENTION OF STROKE DYSFUNCTION BY ACE INHIBITION

这是一项研究醛固酮及其受体作用的提案。 与钾、血管紧张素转换酶II和活性氧的相互作用 (ROS)在卒中易感人群血管病理发展中的作用 自发性高血压大鼠(SHRSP)。我们之前已经 发现肾素-血管紧张素系统起着中心作用 在这些患者的肾和脑血管病变的发展中 不受血压影响的动物。海流 提案是基于我们的观察结果，即长期给药 盐皮质激素受体拮抗剂可显著延缓 在生理盐水中卒中和恶性肾硬化的发展 饮用SHRSP对血压几乎没有影响(如果有的话)。我们 最近发现，ROS的清道夫可以延长生存时间 在这些动物中，并将减少蛋白尿的条件下 血管紧张素转换酶抑制和醛固酮输注。免疫组织化学染色检测 饮用盐水的自发性高血压大鼠的硝基酪氨酸显著升高 与WKY和主动脉超氧阴离子形成的比较 慢性卡托普利治疗可降低SHRSP。这个 拟议的研究将集中在ROS作为损害的调解人 制作。我们还将研究它们之间的相互关系 矿物质皮质激素和增加氯化钾摄入量。这个 后者可以刺激醛固酮的释放，减少血管 SHRSP在高钠摄入时的病变产生，但增强 正常钠摄入量下SHRSP的病变形成。研究将会 以检查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病变的影响 和WKY在可检测循环的条件下 没有醛固酮水平。我们还将研究其影响 用药理手段来中断 肾素-血管紧张素-醛固酮对ROS形成和血管的影响 自发性高血压大鼠的病变发展及其逆转作用 醛固酮或血管紧张素Ⅱ。所获得的信息应定义 醛固酮在大鼠血管损伤中的作用 饮用盐水的SHRSP和对血管的新洞察 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.