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Background: Plasma uric acid has been associated with hypertension in a variety of disorders, and has been shown to be predictive of hypertension. The mechanistic role of uric acid in the development of hypertension is not known however., Method: We tested the hypothesis that uric acid stimulates vascular smooth muscle cell (VSMC) proliferation and oxidative stress by stimulating the vascular renin-angiotensin system (RAS). Rat VSMC were exposed to 0-300 micromol uric acid for 48 h., Results: Uric acid (200 and 300 micromol) stimulated the proliferation of VSMC as measured by thymidine uptake. This effect was prevented by 10(-6) mol losartan or by 10(-6) mol captopril. Incubation of VSMC with uric acid for 48 h also increased angiotensinogen messenger RNA expression and intracellular concentrations of angiotensin II. These responses were also inhibited by losartan and captopril. Increased expression of angiotensinogen mRNA was also inhibited by co-incubation with PD 98059, a mitogen-activated protein (MAP) kinase inhibitor. Uric acid stimulated the production of hydrogen peroxide and 8-isoprostane in VSMC. These increases in oxidative stress indicators were significantly reduced by co-incubating the cells with captopril or losartan. Uric acid also decreased nitrite and nitrate concentrations in the culture medium, an effect that was prevented by losartan and captopril., Conclusion: These results demonstrate that uric acid stimulates proliferation, angiotensin II production, and oxidative stress in VSMC through tissue RAS. This suggests that uric acid causes cardiovascular disorders by stimulating the vascular RAS, and this stimulation may be mediated by the MAP kinase pathway.

This study determined whether or not oxidative stress and vascular dysfunction in fructose-induced hyperinsulinemic rats are associated with activation of the vascular renin-angiotensin system (RAS). Four groups of rats were used. CONT rats were fed normal rat chow, CONT+CAP were fed normal rat chow and given 500 mg/L captopril in their drinking water, fructose-fed rats (FFR) were fed a high-fructose diet and FFR+CAP were fed the high-fructose diet plus captopril in water. After 8 weeks, the vascular reactivity of mesenteric artery segments was measured. Blood was analyzed for insulin, glucose, hydrogen peroxide and 8-isoprostane. Aortic and heart tissue were used for subjected to quantitative reverse transcription-polymerase chain reaction (qRT-PCR) analysis. Systolic blood pressure was significantly higher in FFR (p<0.05), and captopril treatment inhibited the blood pressure increase. Mesenteric artery dose-response curves to acetylcholine were shifted to the right in FFR (p<0.05) and were normal in FFR+CAP. Plasma insulin (p<0.05), hydrogen peroxide (p<0.02) and 8-isoprostane (p<0.05) were increased in FFR. Captopril treatment reducd hydrogen peroxide and 8-isoprostane concentrations. Aortic tissue mRNA expression levels were increased for angiotensin-converting enzyme (ACE, p<0.05), angiotensin type 1 receptor (AT1R, p<0.02), NOX4 (p<0.02) and VCAM-1 (p<0.05) in FFR aortic samples. Captopril treatment reduced AT1R, NOX4 and VCAM-1 expression in FFR to levels not different from CONT. Similar changes in heart tissue mRNA expression for angiotensinogen, AT1R and NOX4 were also observed. These results demonstrate that vascular RAS is upregulated in FFR and support the hypothesis that vascular RAS mediates vascular dysfunction and vascular oxidative stress in FFR.

Background: Fish oil has been shown to improve blood pressure (BP) in some disease states by an unknown mechanism. We tested the ability of fish oil to prevent vascular dysfunction in fructose-fed rats, a model of insulin resistance and hypertension., Methods: Rats were placed on three diets: 1) regular rat diet (control); 2) diet containing 60% fructose (FFR); or 3) diet containing 60% fructose and 4.4% fish oil (FFR+FO). After 8 weeks, blood, heart, aorta, and mesenteric artery tissue were collected from each animal. Secondary branch segments of mesenteric arteries were isolated for vascular reactivity studies., Results: Systolic BP increased significantly in the FFR but was reduced to control levels by the addition of fish oil to the diet. In the mesenteric artery segments from FFR, the dose-response curves to acetylcholine were significantly shifted to the right compared with those of control rats and rats on the fish oil diet. Expression of endothelial nitric oxide synthase (eNOS) protein and mRNA was reduced in the FFR aortas and hearts, and this reduction was reversed by the fish oil. Dietary fish oil prevented the hyperlipidemia that occurred in the FFR but did not prevent hyperinsulinemia. Plasma concentrations of hydrogen peroxide, 8-isoprostane, and monocyte chemoattractant protein-1 were significantly elevated in the FFR and were significantly lower in the FFR treated with fish oil., Conclusions: These results demonstrate that dietary fish oil prevents vascular dysfunction in FFR and that this effect of fish oil is associated with increased eNOS expression and decreased oxidative stress.