Background-Atherosclerotic renovascular disease may augment deterioration of renal function and ischemic nephropathy compared with other causes of renal artery stenosis (RAS), but the underlying mechanisms remain unclear. This study was designed to test the hypothesis that concurrent early atherosclerosis and hypoperfusion might have greater early deleterious effects on the function and structure of the stenotic kidney. Methods and Results-Regional renal hemodynamics and function at baseline and during vasoactive challenge (acetylcholine or sodium nitroprusside) were quantified in vivo in pigs by electron-beam computed tomography after a 12-week normal (nϭ7) or hypercholesterolemic (HC, nϭ7) diet, RAS (nϭ6), or concurrent HC and a similar degree of RAS (HCϩRAS, nϭ7). Flash-frozen renal tissue was studied ex vivo. Basal cortical perfusion and single-kidney glomerular filtration rate (GFR) were decreased similarly in the stenotic RAS and HCϩRAS kidneys, but tubular fluid reabsorption was markedly impaired only in HCϩRAS. Perfusion responses to challenge were similarly blunted in the experimental groups. Stimulated GFR increased in normal, HC, and RAS (38.3Ϯ3.6%, 36.4Ϯ7.6%, and 60.4Ϯ9.3%, respectively, PϽ0.05), but not in HCϩRAS (6.5Ϯ15.1%). These functional abnormalities in HCϩRAS were accompanied by augmented perivascular, tubulointerstitial, and glomerular fibrosclerosis, inflammation, systemic and tissue oxidative stress, and tubular expression of nuclear factor-B and inducible nitric oxide synthase. Conclusions-Early chronic HCϩRAS imposes distinct detrimental effects on renal function and structure in vivo and in vitro, evident primarily in the tubular and glomerular compartments. Increased oxidative stress may be involved in the proinflammatory and progrowth changes observed in the stenotic HCϩRAS kidney, which might potentially facilitate the clinically observed progression to end-stage renal disease.

Abstract-In this review, we examine the possibility that small increments in angiotensin II are responsible for an increase in blood pressure and maintenance of hypertension through the stimulation of oxidative stress. A low dose of angiotensin II (2 to 10 ng ⅐ kg Ϫ1 ⅐ min Ϫ1 , which does not elicit an immediate pressor response), when given for 7 to 30 days by continuous intravenous infusion, can increase mean arterial pressure by 30 to 40 mm Hg. This slow pressor response to angiotensin is accompanied by the stimulation of oxidative stress, as measured by a significant increase in levels of 8-iso-prostaglandin F 2␣ (F 2 -isoprostane). Superoxide radicals and nitric oxide can combine chemically to form peroxynitrite, which can then oxidize arachidonic acid to form F 2 -isoprostanes. F 2 -isoprostanes exert potent vasoconstrictor and antinatriuretic effects. Furthermore, angiotensin II can stimulate endothelin production, which also has been shown to stimulate oxidative stress. In this way, a reduction in the concentration of nitric oxide (which is quenched by superoxide) along with the formation of F 2 -isoprostanes and endothelin could potentiate the vasoconstrictor effects of angiotensin II. We hypothesize that these mechanisms, which underlie the development of the slow pressor response to angiotensin II, also participate in the production of hypertension when circulating angiotensin II levels appear normal, as occurs in many cases of essential and renovascular hypertension.

To assess the reliability of electron beam computed tomography (EBCT), measurements of single-kidney renal blood flow (RBF), glomerular filtration rate (GFR), and intratubular contrast medium concentration (ITC) of radiographic contrast media were quantified in anesthetized pigs before and after acetylcholine-induced vasodilation and diuresis. EBCT measurements were compared with those obtained with intravascular Doppler and inulin clearance. The capability of EBCT to detect chronic changes in single-kidney function was evaluated in pigs with unilateral renal artery stenosis, and their long-term reproducibility in normal pigs was studied repeatedly at 1-mo intervals. EBCT-RBF (ml/min) correlated with Doppler-RBF as RBF(EBCT) = 45 + 1.07 * RBF(Doppler), r = 0.81. EBCT-GFR (ml/min) correlated with inulin clearance as GFR(EBCT) = 11.7 + 1.02 * GFR(inulin), r = 0.80. During vasodilation, RBF and GFR increased, whereas ITC decreased along the nephron. In renal artery stenosis, single-kidney GFR decreased linearly with the degree of stenosis, and ITC increased along the nephron, indicating increased fluid reabsorption. EBCT-RBF, GFR, and ITC were similar among repeated measurements. This approach might be invaluable for simultaneous quantification of regional hemodynamics and function in the intact kidneys, in a manner potentially applicable to humans.