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.
