1. Role of angiotensin II and oxidative stress in vascular insulin resistance linked to hypertension.
- Author
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Zhou MS, Schulman IH, and Raij L
- Subjects
- Acetylcholine pharmacology, Angiotensin II Type 1 Receptor Blockers pharmacology, Animals, Antioxidants pharmacology, Benzimidazoles pharmacology, Biphenyl Compounds, Blood Pressure, Body Weight, C-Reactive Protein metabolism, Cyclic N-Oxides pharmacology, Disease Models, Animal, Dose-Response Relationship, Drug, Endothelium, Vascular drug effects, Endothelium, Vascular physiopathology, Hypertension drug therapy, Hypertension etiology, Hypertension physiopathology, Insulin metabolism, JNK Mitogen-Activated Protein Kinases metabolism, Male, Nitric Oxide Synthase Type III metabolism, Phosphatidylinositol 3-Kinases metabolism, Phosphorylation, Proto-Oncogene Proteins c-akt metabolism, RNA, Messenger metabolism, Rats, Rats, Inbred Dahl, Receptor, Angiotensin, Type 1 metabolism, Receptor, Angiotensin, Type 2 metabolism, Sodium Chloride, Dietary, Spin Labels, Superoxide Dismutase metabolism, Tetrazoles pharmacology, Vasodilation, Vasodilator Agents pharmacology, Angiotensin II metabolism, Endothelium, Vascular metabolism, Hypertension metabolism, Insulin Resistance, Oxidative Stress drug effects, Signal Transduction drug effects
- Abstract
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.
- Published
- 2009
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