ANG II: Permissive role to maintain vascular relaxation

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Elevated dietary salt intake in normotensive animals leads to impaired relaxation of resistance arteries in response to a variety of vasodilator stimuli. This appears to be mediated by suppression of the renin-angiotensin system (RAS), since it can be prevented by i.v. infusion of a low dose of angiotensin II (ANGII). This project will study the response of the middle cerebral artery (MCA) to vasodilator stimuli in four novel inbred genetic rat strains: 1) Dahl salt sensitive (Dahl S; SS/Mcw) rats, a genetic model of salt sensitive hypertension that exhibits impaired relaxation to vasodilator stimuli and an impaired ability to regulate plasma ANGII levels in response to changes in dietary salt intake; 2) normotensive Brown Norway (BN/Mcw) rats; 3) SS.BN13 consomic rats, with chromosome 13 of BN rat on the Dahl S background; and 4), renin congenic rats, with the Dahl R renin gene on the Dahl S genetic background. These rat strains will be used to test two fundamental hypotheses related to the role of ANGII in maintaining normal vascular relaxation mechanisms. The first hypothesis is that ANGII, acting through its specific receptor subtypes, plays a role in the maintenance of vascular relaxation mechanisms in middle cerebral arteries under normal physiological conditions. The second hypothesis is that the impaired relaxation of the middle cerebral artery to vasodilator stimuli that occurs in Dahl S rats on a low salt diet is due to defective regulation of plasma ANGII levels in these animals. In Aim 1, we will compare the response of isolated middle cerebral arteries to a variety of vasodilator stimuli acting via different signal transduction mechanisms in inbred normotensive BN/Mcw rats, SS/Mcw rats, and SS.BN13 consomic rats on a low salt diet, in order to demonstrate that SS/Mcw rats on low salt diet exhibit impaired relaxation mechanisms that are not shared by BN/Mcw rats, SS.BN13 rats, or other normotensive rat strains e.g., Sprague-Dawley rats, that have been extensively characterized in studies by our laboratory and others. Aim 2 will utilize pharmacological tools, endothelial removal, and measurement of key biochemical mediators of vascular relaxation in order to determine the mechanisms that mediate vascular relaxation in response to vasodilator stimuli in isolated middle cerebral arteries of SS.BN13 consomic rats on a low salt diet, and to identify vascular relaxation mechanisms that are impaired in vessels of SS/Mcw rats on low salt diet. Aim 3 will utilize i.v. infusions of the ANGII receptor antagonists losartan (ATI) and PD123319 (AT2) to determine the role of specific ANGII receptor subtypes in maintaining vascular relaxation mechanisms in the middle cerebral artery under normal physiological conditions in SS.BN13 rats and in renin congenic rats, and to assess the role of specific ANGII receptor subtypes in mediating any protective effect of low dose ANGII infusion to restore normal responses of the middle cerebral artery to vasodilator stimuli in SS/Mcw rats on a low salt diet. The demonstration that ANGII may have a permissive role in maintaining vascular relaxation mechanisms in normotensive animals is a completely new aspect of ANGII's complex physiological role that has only recently been described and is largely unexplored. In this respect, the studies proposed in this project address a conceptually innovative aspect of the physiological role of ANGII in regulating vascular function. When completed, these studies will not only enhance our understanding of the role of ANGII and its receptors in regulating vascular reactivity under normal physiological conditions, but will also provide insight into the mechanisms of the impaired reactivity of resistance vessels to vasodilator stimuli in SS/Mcw rats, a genetic model of salt sensitive hypertension that has many similarities to the salt sensitive forms of hypertension that develop in humans, particularly in African-Americans.