The hyperbilirubinemic Gunn rat is resistant to the pressor effects of angiotensin II

Abstract

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 ⅐ kg Ϫ1 ⅐ day Ϫ1 ) 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 ϳ50% 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 ANG II ACTIVATES THE NADPH oxidase enzyme system and promotes the generation of superoxide anion and other reactive oxygen species (15,25,36,40,43). Such stimulation of superoxide anion contributes significantly to the vasoconstrictive and pressor effects of ANG II, as demonstrated by studies that use antioxidants including those that scavenge the superoxide anion (25,36,40,43). Indeed, it is generally accepted that systemic hypertension induced by the chronic administration of ANG II in rodents arises, at least in part, from the generation of superoxide anion as NADPH oxidase is activated by ANG II (25,36,40,43).Our prior studies as well as the studies of others demonstrate that systemic administration of ANG II leads to marked upregulation of heme oxygenase-1 (HO-1) (4, 15, 49). HO is the rate-limiting enzyme in the degradation of heme, enabling the conversion of heme to biliverdin, in the course of which carbon monoxide evolves and iron is liberated from the heme ring; subsequently, biliverdin is converted to bilirubin (2,3,31,32,39). The HO-1 isoform is rapidly induced by diverse stimuli and often confers a cytoprotective, anti-inflammatory, and vasorelaxant effect (2,3,31,32,39). The induction of HO-1 following the administration of ANG II likely exerts a countervailing, vasorelaxant effect: prior upregulation of HO-1 reduces the rise in systemic blood pressure induced by ANG II, whereas inhibition of HO activity exace...

Hyperbilirubinemia Reduces the Streptozotocin-Induced Pancreatic Damage through Attenuating the Oxidative Stress in the Gunn Rat

“…STZ, taken up via GLUT2, induced cell death mainly through alkylation of DNA in target tissues (Bennett and Pegg 1981), which is related to NO generation during the STZ metabolic process (Pflueger et al 2005). The STZ-induced pancreatic damage could be reduced with NO scavengers (Kröncke et al 1995).…”

“…NADPH oxidase causes alterations in signal transduction, insulin secretion, insulin action, and cell proliferation in the diabetic condition (Newsholme et al 2007), suggesting that it may be a target for intervention to improve insulin sensitivity in diabetes mellitus. The Gunn rat lacks the enzyme uridine-diphosphate glucuronosyltransferase that is responsible for conjugation and subsequent excretion of bilirubin into the bile, thus exhibiting elevation of plasma bilirubin (Pflueger et al 2005).…”

Oral phycocyanobilin may diminish the pathogenicity of activated brain microglia in neurodegenerative disorders

“…75 It seems likely that PCB could act both centrally and peripherally to ameliorate hypertension -by boosting the vasorelaxant bioefficacy of nitric oxide in resistance arteries (consequent to suppression of arterial superoxide production), and by antagonizing the central pressor actions of angiotensin II. Indeed, it is notable that Gunn rats, a genetic variant in which free bilirubin levels are constitutively elevated, are much less responsive to the longterm hypertensive impact of angiotensin II infusion, 76 and that the prevalence of hypertension in middle-aged subjects with Gilbert syndrome appears to be anomalously low. 7 Moreover, it seems likely that long term use of PCB could lower stroke risk -both through an antihypertensive action, and by protecting the bioefficacy of the nitric oxide produced by cerebrovascular endothelium.…”

Hyperbilirubinemia and Intermittent Lower Urinary Tract Dysfunction: A Story

“…In this work, Stojanović et al concluded that "hyperbilirubinemia might be a predisposing factor for intermittent lower urinary tract dysfunction in children [1]." I have some discussions on this work.…”

“…Sir, I read the recent publication on hyperbilirubinemia and urinary tract dysfunction with great interest [1]. In this work, Stojanović et al concluded that "hyperbilirubinemia might be a predisposing factor for intermittent lower urinary tract dysfunction in children [1]."…”