Abstract-The angiotensin II (Ang II) slow-pressor response entails an increase in mean arterial pressure and reactive oxygen species. We used double-stranded interfering RNAs (siRNAs) in Sprague Dawley rats in vivo to test the hypothesis that an increase in the p22 phox component of NADPH oxidase is required for this response. Reactive oxygen species were assessed from excretion of 8-isoprostane prostaglandin F 2␣ and blood pressure by telemetry. Two siRNA sequences to p22 phox (sip22 phox ) reduced mRNA Ͼ85% in cultured vascular smooth muscle cells. Rats received rapid (10 second) IV injections (50 to 100 g) Key Words: hypertension, arterial Ⅲ arterioles Ⅲ oxidative stress Ⅲ kidney A ngiotensin II (Ang II) has been assigned a critical role in the generation and complications of human essential hypertension, yet plasma renin activity and plasma concentrations of Ang II are not remarkably elevated. 1 Mice, 2 rats, 3,4 rabbits, 5 or humans 6 infused with Ang II at doses that are initially subpressor develop a "slow-pressor response" in which the blood pressure (BP) increases progressively despite plasma Ang II concentrations that are increased only moderately. 3 The kidney is implicated in the slow-pressor response, because the development of hypertension depends on salt intake. 3 Moreover, rats or rabbits infused with Ang II have enhanced renal vasoconstriction to Ang II 5,7 despite downregulation of Ang II type 1 receptors.Reactive oxygen species (ROS) and superoxide anion (O 2 ⅐Ϫ ) have been implicated in the development of hypertension in the Ang II slow-pressor model, because hypertension is prevented by antioxidant molecules, such as a permeabilized form of superoxide dismutase or tempol, which is an superoxide dismutase mimetic nitroxide. 2,4,5,8 Infusions of Ang II increase the activity of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in blood vessels 9 and the kidney cortex. 4,10,11 This complex enzyme, which was first described in phagocytes and, later, in blood vessels and the kidney, is composed of membrane-associated components of the flavoprotein catalytic core, gp91phox (now named Nox-2) and p22phox . 12 Activation requires phosphorylation of p47 phox 13and its assembly with p67 phox 14 and Rac-1 at the membrane. 12 Homologues of Nox-2 include Nox-1, which has been characterized in vascular smooth muscle cells (VSMCs), 9 and Nox-4, which has been characterized in the kidney. 15 VSMCs and kidneys have the phagocytic NADPH oxidase components. 12 p22 phox is expressed in the thick ascending limb, macula densa, distal convoluted tubule, collecting ducts, vasculature, and interstitial fibroblasts of the kidney. 16 It is believed to dock the enzyme complex in the cell membrane and stabilize Nox proteins. 12 There is colocalization of p22 phox and O 2 ⅐Ϫ generation in atherosclerotic plaques from human blood vessels. 17 The p22 phox component is upregulated in the
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