title: Hypoxia-induced reactive oxygen species downregulate ETB receptor-mediated contraction of rat pulmonary arteries.
abstract: 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 endothelin (ET) type B (ETB) receptor-mediated vasocontraction in lungs was determined. In rat intrapulmonary (approximately 0.63 mm ID) arteries, contraction induced by IRL-1620 (a selective ETB receptor agonist) was significantly attenuated after 4 h of hypoxia (30 mmHg Po2) compared with normoxic control (140 mmHg Po2). The effect was abolished by tiron, a scavenger of superoxide anions, but not by polyethylene glycol (PEG)-conjugated catalase, which scavenges H2O2. The hypoxic effect on ETB receptor-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 H2O2, attenuated the vasoconstriction induced by IRL-1620. Confocal study showed that hypoxia increased ROS production in pulmonary arteries that were scavenged by PEG-conjugated SOD. In endothelium-intact pulmonary arteries, the ETB receptor protein was reduced after 4 h of exposure to hypoxia, exogenous superoxide anions, or ET-1. BQ-788, a selective ETB receptor antagonist, prevented these effects. ET-1 production was stimulated in endothelium-intact arteries after 4 h of exposure to hypoxia or exogenous superoxide anions. This effect was blunted by PEG-conjugated SOD. These results demonstrate that exposure to hypoxia attenuates ETB receptor-mediated contraction of rat pulmonary arteries. A hypoxia-induced production of superoxide anions may increase ET-1 release from the endothelium and result in downregulation of ETB receptors on smooth muscle.
authors.affiliation: Dept. of Physiology and Pathophysiology, Peking Univ. Health Science Center, 38 Xue Yuan Rd., Beijing 100083, China.
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Wang
authors.forename: Mei
authors.initials: M
authors.lastname: Tong
authors.forename: Shashi
authors.initials: S
authors.lastname: Chinta
authors.forename: J Usha
authors.initials: JU
authors.lastname: Raj
authors.forename: Yuansheng
authors.initials: Y
authors.lastname: Gao
mesh_terms: D000818:Animals; D015536:Down-Regulation; D019332:Endothelin-1 / Q000494:pharmacology; D016232:Endothelins / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D006976:Hypertension, Pulmonary / Q000150:complications / Q000378:metabolism; D000860:Hypoxia / Q000378:metabolism*; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects*; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D010446:Peptide Fragments / Q000494:pharmacology; D011651:Pulmonary Artery / Q000378:metabolism; D011652:Pulmonary Circulation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*; D044023:Receptor, Endothelin B / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism; D014661:Vasoconstriction / Q000502:physiology*
chemical_list: D019332:Endothelin-1; D016232:Endothelins; D010446:Peptide Fragments; D017382:Reactive Oxygen Species; D044023:Receptor, Endothelin B; D013481:Superoxides; C074308:sovateltide