(Hypertension. 2001;37:414.)
© 2001 American Heart Association, Inc.
Scientific Contributions |
Endothelial Dysfunction and Xanthine Oxidoreductase Activity in Rats With Human Renin and Angiotensinogen Genes
From the Institute of Biomedicine, Department of Pharmacology and Toxicology (E.M.A.M., Z.J.C., K.N., H.V.) and Department of Medical Chemistry (R.L.), University of Helsinki, Helsinki, Finland; Department of Medicine, Helsinki University Central Hospital and Minerva Institute for Medical Research, Helsinki, Finland (I.T.); and Franz Volhard Clinic, Medical Faculty of the Charité, Humboldt University of Berlin and Max Delbrück Center for Molecular Medicine, Berlin, Germany (D.N.M., A.F., U.G., D.G., F.C.L.).
Correspondence to Eero Mervaala, MD, PhD, Assistant Professor, Institute of Biomedicine, Department of Pharmacology and Toxicology, PO Box 8, FIN-00014 University of Helsinki, Finland. E-mail eero.mervaala{at}helsinki.fi
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 F2
, 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 F2 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.
Key Words: endothelium • superoxide • arachidonic acid • xanthine • endothelin • angiotensin II • receptors, angiotensin II
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