Endothelial Dysfunction and Xanthine Oxidoreductase Activity in Rats With Human Renin and Angiotensinogen Genes

• Published in: Hypertension (Dallas, Tex. 1979) Tex. 1979), 2001-02, Vol.37 (2, Part 2 Suppl), p.414-418
• Main Authors: Mervaala, Eero M.A, Cheng, Zhong Jian, Tikkanen, Ilkka, Lapatto, Risto, Nurminen, Kaisa, Vapaatalo, Heikki, Müller, Dominik N, Fiebeler, Anette, Ganten, Ursula, Ganten, Detlev, Luft, Friedrich C
• Format: Article
• Language: English
• Subjects: Acetylcholine - pharmacology; Angiotensin II - pharmacology; Angiotensinogen - genetics; Animals; Animals, Genetically Modified; Antihypertensive Agents - therapeutic use; Arterial hypertension. Arterial hypotension; Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Clinical manifestations. Epidemiology. Investigative techniques. Etiology; Dinoprost - analogs & derivatives; Dinoprost - pharmacology; Disease Models, Animal; Endothelium, Vascular - drug effects; Endothelium, Vascular - physiopathology; F2-Isoprostanes; Humans; Hypertension - drug therapy; Hypertension - genetics; Hypertension - metabolism; Ketone Oxidoreductases - biosynthesis; Male; Medical sciences; Nitrates - urine; Nitrites - urine; Nitroprusside - pharmacology; Norepinephrine - pharmacology; Rats; Rats, Sprague-Dawley; Renal Artery - drug effects; Renin - genetics; Superoxide Dismutase - pharmacology; Tetrazoles - therapeutic use; Valine - analogs & derivatives; Valine - therapeutic use; Valsartan; Vasoconstrictor Agents - pharmacology; Vasodilation
• ISSN: 0194-911X; 1524-4563
• DOI: 10.1161/01.hyp.37.2.414

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 double-transgenic 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.