The goal is to investigate the mechanisms by which the renin-angiotensin system (RAS) causes changes in intrarenal perfusion and tubular filtration-reabsorption dynamics. Renal artery stenosis in swine is predicted to stimulate angiotensin II (Ang II) production that stimulates superoxide isoprostane and endothelin (ET) production. Regional production of these vasoconstrictor agents will cause cortical ischemia with relative preservation of medullary perfusion. Electron beam computerized tomography (EBCT), a non-invasive x-ray, 3-dimentional tomographer (Imatron c-150) with high temporal resolution, has been developed recently and will be used to define changes in intrarenal blood flow and tubular flow patterns. A computerized analysis of vascular casts of microfil will help localize changes in the microcirculation.
Aim # 1 examines changes in intrarenal hemodynamics and relate them with components of the RAS / oxidative stress cascade and ET in the stenotic and contralateral kidneys of pigs with 2-kidney-1-clip Goldblatt hypertension.
Aim # 2 determines if reestablishing blood flow to the stenotic kidney normalizes renal blood flow and its intrarenal distribution in both the stenotic and control kidneys. Unclipping is expected to rapidly normalize arterial pressure is related to changes in the RAS and pressure natriuresis.
Aim # 3 assesses intrarenal hemodynamics and status of the RAS/oxidative stress cascades in humans with focal unilateral renovascular stenosis. The human results are compared with measures in the swine model of 2-kidney-1 kidney clip hypertension.
Aim # 4 examines swine with 2 kidney and 1 kidney clip hypertension with interventions to dissect causal relations between the RAS and / or oxidative stress and intrarenal flows.
Aim # 5 is to characterize hypertension in swine produced by low dose Ang II infusion and the roles of oxidative stress and ET in the pathogenesis.
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