The Dahl salt-sensitive (SS) rat model develops hypertension that is associated with activation of the renin-angiotensin-aldosterone system resulting in increases of angiotensin II which leads to increases in aldosterone levels. Aldosterone, thought to be mainly synthesized in the adrenal gland, is also synthesized in the vasculature, in part, controlled by angiotensin II and participates in the development of vascular hypertrophy. However, little is known about the mechanism(s) associated with the vasculopathic effects of aldosterone on the vasculature. We hypothesize that the vasculopathic effect of aldosterone is a direct effect of aldosterone on cardiac or renal tissue and that high salt sensitizes tissue to aldosterone-induced vascular injury.
The specific aims are: (1) to determine the vasculopathic effect of aldosterone in Dahl salt-sensitive and salt-resistant rats;(2) to determine whether the prostanoids contribute to the vascular injury induced by aldosterone by specifically: (a) determining whether cyclooxygenase (COX) inhibitors prevent or reduce vascular damage induced by aldosterone and (b) assessing whether endothelial dysfunction induced by aldosterone in rats is due to vasoconstrictor prostanoids, isoprostanes and prostacyclin (PGI2) acting via thromboxane (TXA2) receptors. To address the first aim, rats will be fed either a low or high salt (HS) diet in the presence of aldosterone, eplerenone (100mg/kg/day), apocynin (1.5 mM/day), or AMT in their drinking water for 4 weeks. BP and HR will be monitored by telemetry. Tissue and blood samples will be collected for analysis of aldosterone, PGI2, TXA2, isoprostanes, NO levels. Tissue levels of COX, and prostaglandin synthases (i.e., PGH2/PGG2, PGI2) using microarray analysis and histopathology on selected tissues (heart, kidney) and vasculature (aorta) will also be assessed. To address the second aim, inhibitors of COX, PGI2 synthesis, and TXA2 receptor activity will be tested. Analysis of plasma/urinary levels of isoprostane, urinary protein, and gene and protein expression of the subunits of NAD(P)H oxidase will be conducted. Understanding of pathophysiological mechanisms associated with vasculopathic effects of aldosterone will significantly aid in the development of therapeutic interventions in the treatment of several diseases conditions including stroke, congestive heart failure, hypertension and hyperaldosteronism.
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