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1 Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing, China
2 Los Angeles Biomedical Research Institute, Division of Neonatology, Harbor-UCLA Medical Center, Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA, USA
3 Ministry of Education, Key Laboratory of Molecular Cardiovascular Sciences (Peking University), Beijing, China; Los Angeles Biomedical Research Institute, Division of Neonatology, Harbor-UCLA Medical Center, Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA, USA
* To whom correspondence should be addressed. E-mail: ygao{at}bjmu.edu.cn.
The production of reactive oxygen species (ROS) may be increased during hypoxia in pulmonary arteries. In this study, the role of ROS in the effect of hypoxia on ETB receptor-mediated vasocontraction in lungs was determined. In rat intrapulmonary arteries (inner diameter: ~0.63 mm), contraction induced by IRL-1620 (a selective ETB receptor agonist) was significantly attenuated by 4h hypoxic exposure in comparison to normoxic control (Po2: 30 mmHg vs. 140 mmHg). The effect was abolished by tiron, a scavenger of superoxide anions, but not by polyethylene glycol-conjugated catalase, which scavenges hydrogen peroxide. The hypoxic effect on ETB-mediated vasoconstriction was also abolished by endothelium denudation but not by nitro-L-arginine and indomethacin. Exposure for 4 h to exogenous superoxide anions but not to hydrogen peroxide attenuated the vasoconstriction induced by IRL-1620. Confocal study showed that hypoxia increased the production of ROS in pulmonary arteries, which were scavenged by polyethylene glycol-conjugated superoxide dismutase (PEG-SOD). In pulmonary arteries with endothelium, the ETB receptor protein was reduced after 4 h exposure to hypoxia, exogenous superoxide anions, or endothelin-1. BQ-788, a selective ETB receptor antagonist, prevented these effects. The production of endothelin-1 was stimulated in the arteries with endothelium after 4 h exposure to hypoxia or exogenous superoxide anions. This effect was blunted by PEG-SOD. These results demonstrate that exposure to hypoxia attenuates ETB-mediated contraction of rat pulmonary arteries. A hypoxia-induced production of superoxide anions may increase the release of endothelin-1 from the endothelium and result in downregulation of ETB receptors on smooth muscle.
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