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(Hypertension. 2006;47:238.)
© 2006 American Heart Association, Inc.

Original Articles

RNA Silencing In Vivo Reveals Role of p22^phox in Rat Angiotensin Slow Pressor Response

Paul Modlinger; Tinatin Chabrashvili; Pritomhinder S. Gill; Margarida Mendonca; David G. Harrison; Kathy K. Griendling; Min Li; Julie Raggio; Anton Wellstein; Yifan Chen; William J. Welch; Christopher S. Wilcox

From the Division of Cardiology (D.G.H., K.K.G.), Emory University, Atlanta, Ga; Angiogenesis Section (P.S.G., A.W., Y.C., W.J.W., C.W.), Lombardi Cancer Center, and Cardiovascular-Kidney Institute and Division of Nephrology and Hypertension (P.M., T.C., P.S.G., M.M., M.L., J.R., Y.C., W.J.W., C.S.W.) Georgetown University, Washington, DC.

Correspondence to Christopher S. Wilcox, Georgetown University Medical Center–PHC F6003, 3800 Reservoir Rd, NW, Washington, DC 20007. E-mail wilcoxch{at}georgetown.edu

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 F₂ and blood pressure by telemetry. Two siRNA sequences to p22^phox (sip22^phox) reduced mRNA >85% in cultured vascular smooth muscle cells. Rats received rapid (10 second) IV injections (50 to 100 µg) of 1 of 2 different sip22^phox, control siRNA, or vehicle (TransIt in saline) during 14 day SC infusions of Ang II (200 ng · kg^–1 · min^–1) or sham infusions. In both groups, sip22^phox, relative to control siRNA, led to significant (P<0.001; 50%) reductions in expression of p22^phox mRNA and protein and of NADPH oxidase activity in the kidney cortex. In Ang II–infused rats, sip22^phox decreased protein expression for Nox-1, -2, and -4 but increased p47^phox. Three days after sip22^phox, conscious rats infused with Ang II had a reduced excretion of 8-isoprostane (10±1 versus 19±2 pg · 24 h^–1; P<0.01) and a reduced mean arterial pressure (142±5 versus 168±4 mm Hg; P<0.005). An increase in p22^phox is required for increased renal NADPH oxidase activity, expression of Nox proteins and oxidative stress, and contributes 50% to hypertension during an Ang II slow-pressor response.

Key Words: hypertension, arterial • arterioles • oxidative stress • kidney

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