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Am J Physiol Renal Physiol 288: F552-F558, 2005. First published November 9, 2004; doi:10.1152/ajprenal.00278.2004
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The hyperbilirubinemic Gunn rat is resistant to the pressor effects of angiotensin II

Axel Pflueger,1 Anthony J. Croatt,1 Timothy E. Peterson,2 Leslie A. Smith,2 Livius V. d'Uscio,2 Zvonimir S. Katusic,2,3 and Karl A. Nath1

1Division of Nephrology, Department of Internal Medicine, 2Department of Anesthesiology, and 3Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, Minnesota

Submitted 30 July 2004 ; accepted in final form 4 November 2004

ANG II induces vasoconstriction, at least in part, by stimulating NADPH oxidase and generating reactive oxygen species. ANG 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 ANG II. Our in vivo studies used the hyperbilirubinemic Gunn rat which is deficient in the enzyme uridine diphosphate glucuronosyl transferase, the latter enabling the excretion of bilirubin into bile. ANG II (0.5 mg·kg–1·day–1) or saline vehicle was administered by osmotic minipump to control and Gunn rats for 4 wk. The rise in systolic blood pressure induced by ANG II, as observed in control rats, was markedly reduced in Gunn rats, the latter ~50% less at 3 and 4 wk after the initiation of ANG II infusion. The chronic administration of ANG II also impaired endothelium-dependent relaxation responses in control rats but not in Gunn rats. As assessed by the tetrahydrobiopterin/dihydrobiopterin ratio, ANG II induced oxidative stress in the aorta in control rats but not in Gunn rats. Heightened generation of superoxide anion in aortic rings in ANG II-infused rats and by vascular smooth muscle cells exposed to ANG II was normalized by bilirubin in vitro. We conclude that the pressor and prooxidant effects of ANG II are attenuated in the hyperbilirubinemic Gunn rat, an effect which, we speculate, may reflect, at least in part, the scavenging of superoxide anion by bilirubin.

NADPH oxidase; heme oxygenase; nitric oxide; endothelial function


Address for reprint requests and other correspondence: K. A. Nath, Mayo Clinic, 200 First St., SW, Guggenheim 542, Rochester, MN 55905 (E-mail: nath.karl{at}mayo.edu)




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