thromboxane-b2 and Hypertrophy--Right-Ventricular

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.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Animals, Newborn; Blotting, Western; Carbazoles; Cells, Cultured; Cyclooxygenase Inhibitors; Dinoprost; Endothelin-1; F2-Isoprostanes; Furans; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Immunohistochemistry; Lung; Muscle, Smooth, Vascular; Oxygen; Prostaglandin Antagonists; Prostaglandin-Endoperoxide Synthases; Pulmonary Artery; Rats; Receptors, Thromboxane; Thromboxane B2; Up-Regulation; Vasoconstrictor Agents