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This Article Full Text Full Text (PDF) All Versions of this Article: 296/3/H833    most recent 01096.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Zhou, M.-S. Articles by Raij, L. Search for Related Content PubMed PubMed Citation Articles by Zhou, M.-S. Articles by Raij, L.

Role of angiotensin II and oxidative stress in vascular insulin resistance linked to hypertension

Nephrology-Hypertension Section, Veterans Affairs Medical Center, and Division of Nephrology and Hypertension and Vascular Biology Institute, Miller School of Medicine, University of Miami, Miami, Florida

Submitted 13 October 2008 ; accepted in final form 15 January 2009

Insulin activation of the phosphatidylinositol 3-kinase (PI3K) pathway stimulates glucose uptake in peripheral tissues and synthesis of nitric oxide (NO) in the endothelium. Insulin resistance (IR) and hypertension frequently coexist, particularly among individuals with salt-sensitive hypertension. The mechanisms underlying this association are poorly understood. We investigated these mechanisms in a model of salt-sensitive hypertension in which we have previously shown that endothelial dysfunction is mediated by superoxide anion (O₂^–) linked to local ANG II. Dahl salt-sensitive rats were fed, for 6 wk, a normal salt diet (NS; 0.5% NaCl), high-salt diet (HS; 4% NaCl), HS plus the ANG II type 1 receptor (AT₁R) blocker (ARB) candesartan (10 mg·kg^–1·day^–1), or HS plus the antioxidant tempol (172 mg/l in drinking water). Hypertensive (mean arterial pressure: 145 ± 4 vs. 102 ± 5 mmHg in NS, P < 0.05) rats manifested increased aortic AT₁R mRNA (210%) and protein (101%) expression and O₂^– production (104%) and impaired endothelium-dependent relaxation (EDR) to acetylcholine [maximal response (E_max): 68 ± 9 vs. 91 ± 8% in NS, P < 0.05]. ARB or tempol normalized O₂^– and EDR despite that they did not normalize mean arterial pressure, which was reduced only 25%. Hypertensive rats manifested metabolic IR (36% reduction in the glucose infusion rate by insulin clamp), impaired NO-mediated insulin-induced EDR (E_max: 12 ± 5 vs. 32 ± 4% in NS, P < 0.05), and impaired insulin activation of PI3K/endothelial NO synthase. ARB or tempol improved insulin-mediated EDR, PI3K, Akt/ endothelial NO synthase phosphorylation, and metabolic IR (all P < 0.05). This study provides insight into the mechanisms that underlie the association between metabolic and hypertensive cardiovascular diseases and support the notion that O₂^– overproduction linked to tissue ANG II interferes with shared insulin signaling pathways in metabolic and cardiovascular tissues.

endothelial function; salt sensitivity