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(2)(-)) 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(1)R) 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 AT(1)R mRNA (210%) and protein (101%) expression and O(2)(-) 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 O(2)(-) 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 O(2)(-) overproduction linked to tissue ANG II interferes with shared insulin signaling pathways in metabolic and cardiovascular tissues.
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