Endothelial dysfunction and xanthine oxidoreductase activity in rats with human renin and angiotensinogen genes

We examined whether xanthine oxidoreductase (XOR), a hypoxia-inducible enzy me capable of generating reactive oxygen species, is involved in the onset of angiotensin (Ang) II-induced vascular dysfunction in double-transgenic r ats (dTGR) harboring human renin and human angiotensinogen gents. In 7-week -old hypertensive dTGR, the endothelium-mediated relaxation of noradrenalin e (NA)-precontracted renal arterial rings to acetylcholine (ACh) in vitro w as markedly impaired compared with Sprague Dawley rats. Preincubation with superoxide dismutase (SOD) improved the endothelium-dependent vascular rela xation, indicating that in dTGR, endothelial dysfunction is associated with increased superoxide formation. Preincubation with the XOR inhibitor oxypu rinol also improved endothelium-dependent Vascular relaxation. The endothel ium-independent relaxation to sodium nitroprusside was similar in both stra ins. In dTGR, serum 8-isoprostaglandin F-2 alpha, a vasoconstrictor and ant inatriuretic arachidonic acid metabolite produced by oxidative stress, was increased by 100%, and the activity of XOR in the kidney was increased by 4 0%. Urinary nitrate plus nitrite (NOx) excretion, a marker of total body NO generation, was decreased by 85%. Contractile responses of renal arteries to Ang II, endothelin-1 (ET-1), and NA were decreased in dTGR, suggesting h ypertension-associated generalized changes in the vascular function rather than a receptor-specific desensitization. Valsartan (30 mg/kg PO for 3 week s) normalized blood pressure, endothelial dysfunction, and the contractile responses to ET-1 and NA. Valsartan also normalized serum 8-isoprostaglandi n F-2 alpha levels, renal XOR activity, and, to a degree, NOx excretion. Th us, overproduction of Ang II in dTGR induces pronounced endothelial dysfunc tion, whereas the sensitivity of vascular smooth muscle cells to nitric oxi de is unaltered. Ang II-induced endothelial dysfunction is associated with increased oxidative stress and vascular xanthine oxidase activity.