The hyperbilirubinemic Gunn rat is resistant to the pressor effects of angiotensin II.
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 x kg(-1) x 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 approximately 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.
Pflueger
Axel
A
Division of Nephrology, Department of Internal Medicine, Mayo Clinic, 200 First St., SW, Guggenheim 542, Rochester, MN 55905, USA.
Croatt
Anthony J
AJ
Peterson
Timothy E
TE
Smith
Leslie A
LA
d'Uscio
Livius V
LV
Katusic
Zvonimir S
ZS
Nath
Karl A
KA
D000109:Acetylcholine / Q000494:pharmacology; D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects; D001708:Biopterins / Q000031:analogs & derivatives* / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects*; D001835:Body Weight / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism; D051547:Heme Oxygenase-1; D006932:Hyperbilirubinemia / Q000235:genetics* / Q000503:physiopathology*; D066298:In Vitro Techniques; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D011911:Rats, Gunn; D017208:Rats, Wistar; D013481:Superoxides / Q000378:metabolism; D014662:Vasoconstrictor Agents / Q000494:pharmacology*; D014665:Vasodilator Agents / Q000494:pharmacology
D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D013481:Superoxides; D000804:Angiotensin II; D001708:Biopterins; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C003402:sapropterin; D000109:Acetylcholine