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1 Division of Nephrology, Department of Internal Medicine, Mayo Clinic College of Medicine, Rochester, MN, USA
2 Department of Anesthesiology, Mayo Clinic College of Medicine, Rochester, MN, USA
3 Department of Anesthesiology, Mayo Clinic College of Medicine, Rochester, MN, USA; Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, MN, USA
* To whom correspondence should be addressed. E-mail: nath.karl{at}mayo.edu.
Angiotensin II induces vasoconstriction, at least in part, by stimulating NADPH oxidase and generating reactive oxygen species. Angiotensin II also induces heme oxygenase activity, and bilirubin, a product of such activity, possesses antioxidant properties. We hypothesized that bilirubin, because of its antioxidant properties, may reduce the pressor and prooxidant effects of angiotensin II. Our in vivo studies utilized the hyperbilirubinemic Gunn rat, which is deficient in the enzyme uridine diphosphate glucuronosyl transferase, the latter enabling the excretion of bilirubin into bile. Angiotensin II (0.5 mg/kg/day) or saline vehicle was administered by osmotic minipump to control and Gunn rats for 4 weeks. The rise in systolic blood pressure induced by angiotensin II, as observed in control rats, was markedly reduced in Gunn rats, the latter approximately 50% less at 3 and 4 weeks after the initiation of angiotensin II infusion. The chronic administration of angiotensin II also impaired endothelium-dependent relaxation responses in control rats but not in Gunn rats. As assessed by the tetrahydrobiopterin/dihydrobiopterin ratio, angiotensin II induced oxidative stress in the aorta in control rats but not in Gunn rats. Heightened generation of superoxide anion in aortic rings in angiotensin II-infused rats, and by vascular smooth muscle cells exposed to angiotensin II, were both normalized by bilirubin in vitro. We conclude that the pressor and prooxidant effects of angiotensin II are attenuated in the hyperbilirubinemic Gunn rat, an effect which, we speculate, may reflect, at least in part, the scavenging ofsuperoxide anion by bilirubin.
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