Antihypertensive actions of moderate hyperbilirubinemia: role of superoxide inhibition

Am J Hypertens. 2013 Jul;26(7):918-23. doi: 10.1093/ajh/hpt038. Epub 2013 Mar 12.

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.

Keywords: NADPH oxidase; angiotensin II; bilirubin; blood pressure; heme oxygenase; hypertension.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Acetophenones / administration & dosage*
  • Angiotensin II / administration & dosage*
  • Animals
  • Bilirubin / blood
  • Blood Pressure / physiology*
  • Disease Models, Animal
  • Drug Implants
  • Enzyme Inhibitors
  • Hyperbilirubinemia / blood
  • Hyperbilirubinemia / complications
  • Hyperbilirubinemia / physiopathology*
  • Hypertension / complications
  • Hypertension / drug therapy*
  • Hypertension / enzymology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Superoxides / antagonists & inhibitors*
  • Vasoconstrictor Agents / administration & dosage

Substances

  • Acetophenones
  • Drug Implants
  • Enzyme Inhibitors
  • Vasoconstrictor Agents
  • Superoxides
  • Angiotensin II
  • acetovanillone
  • Bilirubin