title: Antihypertensive actions of moderate hyperbilirubinemia: role of superoxide inhibition.
abstract: BACKGROUND
  Moderate (approximately 2-fold) increases in plasma unconjugated bilirubin levels are able to attenuate the development of angiotensin II (Ang II)-dependent hypertension. To determine the specific role of decreases in superoxide production to the blood pressure-lowering effects of moderate hyperbilirubinemia (MHyB), we performed this study, in which the Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor apocynin was given to Ang II-infused mice in the presence and absence of moderate hyperbilirubinemia.
  
  
  METHODS
  Apocynin (14mM) was administered in the drinking water prior to treatment with UDP-glucuronosyltransferase 1A1 antisense morpholino (16 μg/kg), which was administered by intravenous injection every third day. Treatments were started before the implantation of Ang II-containing minipumps (1μg/kg/min) and continued throughout the protocol.
  
  
  RESULTS
  Ang II infusion increased blood pressure to 145±2mm Hg. Apocynin treatment alone reduced blood pressure to 135±5mm Hg, whereas MHyB alone decreased blood pressure to 118±5mm Hg in Ang II-infused mice. Prior inhibition of NADPH oxidase with apocynin did not result in a further decrease in blood pressure in MHyB mice, which averaged 117±3mm Hg (n = 6 mice per group). In aortic preparations, apocynin treatment decreased Ang II-mediated superoxide production from 2433±120 relative light units (RLU)/min/mg to 1851±126 RLU/min/mg (n = 4 mice per group), which was similar to levels observed in MHyB mice alone (1473±132 RLU/min/mg) or in combination with apocynin (1503±115 RLU/min/mg).
  
  
  CONCLUSIONS
  Our results indicate that MHyB lowers blood pressure by a mechanism that is partially dependent on the inhibition of superoxide production.
authors.affiliation: Department of Physiology & Biophysics, Center for Excellence in Cardiovascular-Renal Research, University of Mississippi Medical Center, Jackson, Mississippi, USA. dstec@umc.edu
authors.forename: David E
authors.initials: DE
authors.lastname: Stec
authors.forename: Megan V
authors.initials: MV
authors.lastname: Storm
authors.forename: Brandon E
authors.initials: BE
authors.lastname: Pruett
authors.forename: Monette U
authors.initials: MU
authors.lastname: Gousset
mesh_terms: D000098:Acetophenones / Q000008:administration & dosage*; D000804:Angiotensin II / Q000008:administration & dosage*; D000818:Animals; D001663:Bilirubin / Q000097:blood; D001794:Blood Pressure / Q000502:physiology*; D004195:Disease Models, Animal; D004343:Drug Implants; D004791:Enzyme Inhibitors; D006932:Hyperbilirubinemia / Q000097:blood / Q000150:complications / Q000503:physiopathology*; D006973:Hypertension / Q000150:complications / Q000188:drug therapy* / Q000201:enzymology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D013481:Superoxides / Q000037:antagonists & inhibitors*; D014662:Vasoconstrictor Agents / Q000008:administration & dosage
chemical_list: D000098:Acetophenones; D004343:Drug Implants; D004791:Enzyme Inhibitors; D014662:Vasoconstrictor Agents; D013481:Superoxides; D000804:Angiotensin II; C056165:acetovanillone; D001663:Bilirubin
keywords: NADPH oxidase; angiotensin II; bilirubin; blood pressure; heme oxygenase; hypertension