ROLE OF ENDOTHELIN-1 IN HYPOXIA-INDUCED PULMONARY HYPERTENSION IN NEWBORN PIGLETS. • 426

Abstract

Endothelin-1 (ET-1), a potent vasoconstrictor and mitogen, acts through ETA (constriction) and ETB (dilation) receptors and may be involved in the pathogenesis of pulmonary hypertension (PH). Therefore, we studied in 1-day-old piglets exposed to hypoxia (FiO2 0.10) for 3 or 14 days to induce PH: (1) ET-1 circulating levels in pulmonary artery and veins by radioimmunoassay, (2) pulmonary vascular reactivity to ET-1 using isolated perfused lungs, and (3) ET binding characteristics by examining the concentration dependence of ET-1 and ET-3 binding, and the competitive binding with ET-1, ET-3, BQ-123 (ETA antagonist), BQ-3020 and BQ-788(ETB agonist and antagonist) on membranes from pulmonary arteries (down to 100 μm). ET-1 circulating levels were low and not altered by hypoxia(n=4-11). ET-1 caused a transient dilation and a potent vasoconstriction, and their magnitudes were similar in all groups (n=5). Binding studies revealed a predominance of ETA receptors (>70%). Interestingly, the number of ETB receptors decreased by 40% after 3-day exposure to hypoxia (n=3; p<0.05), while ETA receptors decreased by 50% after 14-day (n=2-4; p<0.05). Furthermore, while binding sites were reduced, the binding affinity increased concomitantly. In conclusion, the reduction in binding sites suggests either downregulation of receptors by locally produced ET-1 or changes in receptor expression. The compensatory increase in binding affinity may explain the maintenance of vascular reactivity in hypoxia. Data suggests an important role for ET-1 in hypoxia-induced PH in the newborn piglet.