Endothelial dysfunction and xanthine oxidoreductase activity in rats with human renin and angiotensinogen genes.
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 F(2alpha), 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 (NO(x)) 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 F(2alpha) levels, renal XOR activity, and, to a degree, NO(x) 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.
Mervaala
E M
EM
Institute of Biomedicine, Department of Pharmacology and Toxicology, Department of Medical Chemistry, University of Helsinki, Helsinki, Finland. eero.mervaala@helsinki.fi
Cheng
Z J
ZJ
Tikkanen
I
I
Lapatto
R
R
Nurminen
K
K
Vapaatalo
H
H
Müller
D N
DN
Fiebeler
A
A
Ganten
U
U
Ganten
D
D
Luft
F C
FC
D000109:Acetylcholine / Q000494:pharmacology; D000804:Angiotensin II / Q000494:pharmacology*; D000808:Angiotensinogen / Q000235:genetics*; D000818:Animals; D030801:Animals, Genetically Modified; D000959:Antihypertensive Agents / Q000627:therapeutic use; D015237:Dinoprost / Q000031:analogs & derivatives / Q000494:pharmacology; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology*; D028441:F2-Isoprostanes; D006801:Humans; D006973:Hypertension / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D007658:Ketone Oxidoreductases / Q000096:biosynthesis*; D008297:Male; D009566:Nitrates / Q000652:urine; D009573:Nitrites / Q000652:urine; D009599:Nitroprusside / Q000494:pharmacology; D009638:Norepinephrine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012077:Renal Artery / Q000187:drug effects; D012083:Renin / Q000235:genetics*; D013482:Superoxide Dismutase / Q000494:pharmacology; D013777:Tetrazoles / Q000627:therapeutic use; D014633:Valine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000068756:Valsartan; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation
D000959:Antihypertensive Agents; D028441:F2-Isoprostanes; D009566:Nitrates; D009573:Nitrites; D013777:Tetrazoles; D014662:Vasoconstrictor Agents; D000808:Angiotensinogen; D000804:Angiotensin II; D009599:Nitroprusside; C075750:8-epi-prostaglandin F2alpha; D000068756:Valsartan; D015237:Dinoprost; D013482:Superoxide Dismutase; D007658:Ketone Oxidoreductases; D012083:Renin; D014633:Valine; D000109:Acetylcholine; D009638:Norepinephrine