Extracellular superoxide enhances 5-HT-induced murine pulmonary artery vasoconstriction

John Q. Liu, Rodney J. Folz

Research output: Contribution to journalArticlepeer-review

50 Scopus citations

Abstract

Accumulating evidence suggests that changes in both 5-hydroxytryptamine (5-HT) receptor activity and in the levels of reactive oxygen species (ROS) play an important role in regulating pulmonary artery (PA) vascular responsiveness, particularly in the setting of pulmonary hypertension. Therefore, we hypothesized that increased levels of superoxide enhance 5-HT-induced PA constriction. With the use of a small-vessel bioassay, 5-HT (0.01-10 μM) induced a concentration-dependent vasoconstriction in isolated wild-type murine intrapulmonary arteries (100-150 μm diameter) that was enhanced by both removal of the endothelium and by treatment with either NG-nitro-L- arginine methyl ester (30 μM) or xanthine (10 μM) + xanthine oxidase (0.005 U/ml). PA isolated from extracellular superoxide dismutase (EC-SOD) knockout mice also showed enhanced constriction. On the other hand, PA constriction to 5-HT was attenuated by either the addition of GR-127935 (0.1 μM, a selective inhibitor of 5-HT1B/1D receptor) or copper/zinc-containing superoxide dismutase (Cu/Zn SOD, 150 U/ml) and in PA isolated from transgenic mice overexpressing human EC-SOD. With the use of both oxidative fluorescent confocal microscopy and lucigenin-enhanced chemiluminescence, superoxide levels were increased significantly after 5-HT-induced PA vasoconstriction. This increase in superoxide levels could be blocked by the exogenous addition of Cu/Zn SOD (150 U/ml) or by apocynin (30 μM, an inhibitor of NADPH oxidase) but was not affected by gp91 phox knockout mice. Overall, our results are consistent with 5-HT increasing vascular smooth muscle superoxide production via an NADPH oxidase pathway that is independent of gp91phox, which leads to increases in extracellular superoxide levels, which in turn enhances 5-HT-induced murine pulmonary vasoconstriction.

Original languageEnglish (US)
Pages (from-to)L111-L118
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume287
Issue number1 31-1
DOIs
StatePublished - Jul 2004

Keywords

  • 5-hydroxytryptamine
  • Extracellular superoxide
  • Murine pulmonary artery
  • Reduced nicotinamide adenine dinucleotide

ASJC Scopus subject areas

  • Physiology
  • Pulmonary and Respiratory Medicine
  • Physiology (medical)
  • Cell Biology

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