The objective of Project 4 is to elucidate mechanisms responsible for changes in vascular and renal function in response to chronic environmental stress and high salt intake. Project 4 will utilize the Dahl salt-sensitive (DS) rat as a model that is sensitive to high salt diet and chronic environmental stress. The DS rat is a well-established model for the salt-dependent low-renin essential hypertension typically found in African Americans. Chronic environmental stress will be produced by recurrent unpredictable, unavoidable exposure to high velocity bursts of air to the head (air jet stress).
Aim 1 will test the hypothesis that air jet stress and high salt diet synergistically increase blood pressure (measured by telemetry) and result in temporal and transcriptional changes in mesenteric resistance arteries and renal inner medulla. In addition, DNA micro arrays will identify genes that are differentially regulated in mesenteric resistance arteries and renal inner medulla under these conditions.
Aim 2 will test the hypothesis that air jet stress and high salt intake decrease vasodilation through a dysfunction of nitric oxide (NO) synthase. Experiments will determine whether air jet stress and/or high salt diet-induces decreases in the production of NO by mesenteric resistance arteries and whether increasing the availability of the substrate for NO synthase, L-arginine, will improve the vasodilating capacity of the mesenteric arteries.
Aim 3 will test the hypothesis that decreased vasodilator capacity during air jet stress and high salt intake is due to increased superoxide production. Experiments will determine whether air jet stress and/or high salt diet increase the production of superoxide by the vasculature and whether inhibiting superoxide production by antioxidant treatment will improve vasodilating capacity of mesenteric arteries.
Aim 4 will test the hypothesis that air jet stress and high salt intake mediate a decrease in vasodilation through an increase in the production or activity of endothelin. We predict that chronic air jet stress will reduce endotheliumdependent vasodilation which will be exacerbated by high salt diet and that dysregulation of the endothelial system is through a loss of functional or bioavailable NO via dysregulation of NO synthase, increased superoxide production, and/or increased endothelin production. We further predict that the balance NO and ET, under these conditions of chronic environmental stress, alters the kidney?s ability to regulate arterial pressure as evidenced by a shift in the pressure-natriuresis relationship in the DS rat.
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