Thromboxane A₂ 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% O₂ for 14 days, a model for human chronic neonatal lung iniury. ET-1 production by d-14 rat pulmonary artery smooth muscle cells in vitro was markedly increased by thromboxane (TX) A₂ receptor agonists and inhibited by a competitive antagonist. We hypothesized that stimulation of the TX A₂ receptor contributed to O₂-mediated PHT in vivo. Newborn rat pups received daily intraperitoneal injections of L670596, a competitive TX A₂ 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% O₂ or air exposure. L670596, but not DFU, prevented 60% O₂-mediated right ventricular and small pulmonary vessel smooth muscle hypertrophy. Lung ET-1 content was significantly reduced by L670596 in 60% O₂-exposed animals. We conclude that TX A₂ receptor activation, though not by TX A₂, 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 A₂ receptor and is a potent inducer of ET-1 production by cultured d-14 rat pulmonary artery smooth muscle cells in vitro.