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

<jats:p> 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 (O<jats:sub>2</jats:sub><jats:sup>−</jats:sup>) 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 (AT<jats:sub>1</jats:sub>R) blocker (ARB) candesartan (10 mg·kg<jats:sup>−1</jats:sup>·day<jats:sup>−1</jats:sup>), 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 AT<jats:sub>1</jats:sub>R mRNA (210%) and protein (101%) expression and O<jats:sub>2</jats:sub><jats:sup>−</jats:sup> production (104%) and impaired endothelium-dependent relaxation (EDR) to acetylcholine [maximal response ( E<jats:sub>max</jats:sub>): 68 ± 9 vs. 91 ± 8% in NS, P < 0.05]. ARB or tempol normalized O<jats:sub>2</jats:sub><jats:sup>−</jats:sup> 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<jats:sub>max</jats:sub>: 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 O<jats:sub>2</jats:sub><jats:sup>−</jats:sup> overproduction linked to tissue ANG II interferes with shared insulin signaling pathways in metabolic and cardiovascular tissues. </jats:p>