Thromboxane A(2) receptors mediate pulmonary hypertension in 60% oxygen-exposed newborn rats by a cyclooxygenase-independent mechanism.
Endothelin-1 (ET-1) mediates the development of pulmonary hypertension (PHT) in newborn rats exposed to 60% O(2) for 14 days, a model for human chronic neonatal lung injury. ET-1 production by d-14 rat pulmonary artery smooth muscle cells in vitro was markedly increased by thromboxane (TX) A(2) receptor agonists and inhibited by a competitive antagonist. We hypothesized that stimulation of the TX A(2) receptor contributed to O(2)-mediated PHT in vivo. Newborn rat pups received daily intraperitoneal injections of L670596, a competitive TX A(2) receptor antagonist, or 5,5-dimethyl-3-(3-fluorophenyl)4-(4-methylsulfonyl)phenyl-2(5H)-furanone (DFU), a cyclooxygenase-2 inhibitor, during 14 days of 60% O(2) or air exposure. L670596, but not DFU, prevented 60% O(2)-mediated right ventricular and small pulmonary vessel smooth muscle hypertrophy. Lung ET-1 content was significantly reduced by L670596 in 60% O(2)-exposed animals. We conclude that TX A(2) receptor activation, though not by TX A(2), caused upregulation of ET-1 and PHT in this model. A likely mediator is the stable lipid peroxidation product, 8-iso-prostane, which acts as an incidental ligand of the TX A(2) receptor and is a potent inducer of ET-1 production by cultured d-14 rat pulmonary artery smooth muscle cells in vitro.
Jankov
Robert P
RP
Canadian Institutes of Health Research Group in Lung Development, Lung Biology Programme, Toronto, Ontario, Canada.
Belcastro
Rosetta
R
Ovcina
Emira
E
Lee
Julia
J
Massaeli
Hamid
H
Lye
Stephen J
SJ
Tanswell
A Keith
AK
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western; D002227:Carbazoles / Q000494:pharmacology; D002478:Cells, Cultured; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015237:Dinoprost / Q000031:analogs & derivatives*; D019332:Endothelin-1 / Q000378:metabolism; D028441:F2-Isoprostanes / Q000378:metabolism / Q000494:pharmacology; D005663:Furans / Q000494:pharmacology; D006976:Hypertension, Pulmonary / Q000378:metabolism / Q000503:physiopathology*; D017380:Hypertrophy, Right Ventricular / Q000503:physiopathology; D007150:Immunohistochemistry; D008168:Lung / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D010100:Oxygen / Q000502:physiology / Q000633:toxicity*; D011448:Prostaglandin Antagonists / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000502:physiology*; D011651:Pulmonary Artery / Q000378:metabolism; D051381:Rats; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors / Q000502:physiology*; D013929:Thromboxane B2 / Q000378:metabolism; D015854:Up-Regulation; D014662:Vasoconstrictor Agents / Q000494:pharmacology
C106876:5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)phenyl-2(5H)-furanone; D002227:Carbazoles; D016861:Cyclooxygenase Inhibitors; D019332:Endothelin-1; D028441:F2-Isoprostanes; D005663:Furans; D011448:Prostaglandin Antagonists; D017482:Receptors, Thromboxane; D014662:Vasoconstrictor Agents; C061299:L 670596; C075750:8-epi-prostaglandin F2alpha; D013929:Thromboxane B2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D015237:Dinoprost; D011451:Prostaglandin-Endoperoxide Synthases; D010100:Oxygen