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

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Item Type:	Article
Title:	Endothelial dysfunction and xanthine oxidoreductase activity in rats with human renin and angiotensinogen genes
Creators Name:	Mervaala, E.M.A., Cheng, Z.J., Tikkanen, I., Lapatto, R., Nurminen, K., Vapaatalo, H., Mueller, D.N., Fiebeler, A., Ganten, U., Ganten, D. and Luft, F.C.
Abstract:	We examined whether xanthine oxidoreductase (XOR), a hypoxia-inducible enzyme capable of generating reactive oxygen species, is involved in the onset of angiotensin (Ang) II-induced vascular dysfunction in doubletransgenic rats (dTGR) harboring human renin and human angiotensinogen genes. In 7-week-old hypertensive dTGR, the endothelium-mediated relaxation of noradrenaline (NA)-precontracted renal arterial rings to acetylcholine (ACh) in vitro was markedly impaired compared with Sprague Dawley rats. Preincubation with superoxide dismutase (SOD) improved the endothelium-dependent vascular relaxation, indicating that in dTGR, endothelial dysfunction is associated with increased superoxide formation. Preincubation with the XOR inhibitor oxypurinol also improved endothelium-dependent vascular relaxation. The endothelium-independent relaxation to sodium nitroprusside was similar in both strains. In dTGR, serum 8-isoprostaglandin F2α, a vasoconstrictor and antinatriuretic arachidonic acid metabolite produced by oxidative stress, was increased by 100%, and the activity of XOR in the kidney was increased by 40%. 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 hypertension-associated generalized changes in the vascular function rather than a receptor-specific desensitization. Valsartan (30 mg/kg PO for 3 weeks) normalized blood pressure, endothelial dysfunction, and the contractile responses to ET-1 and NA. Valsartan also normalized serum 8-isoprostaglandin F2α levels, renal XOR activity, and, to a degree. NOx excretion. Thus, overproduction of Ang II in dTGR induces pronounced endothelial dysfunction, whereas the sensitivity of vascular smooth muscle cells to nitric oxide is unaltered. Ang II-induced endothelial dysfunction is associated with increased oxidative stress and vascular xanthine oxidase activity.
Keywords:	Angiotensin II, Arachidonic Acid, Endothelin, Endothelium, Receptors, Superoxide, Xanthine
Source:	Hypertension
ISSN:	0194-911X
Publisher:	American Heart Association
Volume:	37
Number:	2
Page Range:	414-418
Date:	1 January 2001
Official Publication:	https://doi.org/10.1161/01.HYP.37.2.414
PubMed:	View item in PubMed

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