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1 Department of Physiological Science, University of California, Los Angeles, Los Angeles, CA, USA
2 Division of Endocrinology, Metabolism and Molecular Medicine, Charles R. Drew University, Los Angeles, CA, USA
3 Division of Nephrology and Hypertension, Department of Medicine, Physiology and Biophysics, University of California, Irvine, Irvine, CA, USA
* To whom correspondence should be addressed. E-mail: croberts{at}ucla.edu.
We tested whether consumption of a high-fat, high-sucrose (HFS) diet can affect endothelium-dependent relaxation, if this precedes the development of diet-induced hypertension previously noted in this model, and if it is mediated, in part, by changes in nitric oxide synthase (NOS) and/or NOS regulatory proteins. Female Fischer rats were fed either a HFS diet or standard low-fat, complex-carbohydrate (LFCC) chow starting at 2 months of age for 7 months. Vasoconstrictive response to KCl and phenylephrine was similar in both groups. Vasorelaxation to acetylcholine was significantly impaired in the HFS animals and there were no differences in relaxation to sodium nitroprusside, suggesting that the endothelial dysfunction is due, at least in part, to NO deficiency. HFS consumption decreased protein expression of endothelial NOS in aorta, renal and heart tissues, neuronal NOS in kidney, heart, aorta and brain and inducible NOS in heart and aorta. Caveolin-1 (Cav-1) and soluble guanylate cyclase (sGC-
) protein expression did not change, but AKT protein expression decreased in heart and aorta and increased in kidney tissue. Consumption of HFS diet raised brain carbonyl content and plasma hydrogen peroxide concentration and diminished plasma total antioxidant capacity. Since blood pressure, which is known to eventually rise in this model, was not as yet significantly elevated, the present data suggest that endothelial dysfunction precedes the onset of diet-induced hypertension. The lack of quantitative change in Cav-1 and sGC- protein content indicates that alteration in these proteins is not responsible for the endothelial dysfunction. Thus, NO deficiency, combined with antioxidant/oxidant imbalance, appear to be primary factors in the development of endothelial dysfunction in this model.
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