ENDOTHELIN-1 HAS A DILATOR EFFECT ON NEONATAL PIG PULMONARY VASCULATURE

Endothelin-1 (ET-1), a 21-residue potent vasoconstrictor peptide produced by endothelial cells, was reported to cause vasodilation in the systemic and pulmonary vascular beds. Therefore, in isolated perfused lungs from 7-day-old piglets, we studied the effects and the mechanisms responsible for the dilator effect of ET-1. ET-1 produced a mild transient decrease in perfusion pressure at low doses (< 10(-7) M/g dry lung); at higher doses, a potent long-lasting vasoconstriction was noted. Indeed, the constrictor effect of ET-1 was at least equal to or greater than that of U-44069 and prostaglandin D2 (PGD2). When the vascular tone of the preparation was increased with U-46619, another stable endoperoxide analogue, the dilator response to low doses of ET-1 was increased, while the constrictor response remained unchanged. Indomethacin (2.8 x 10(-6) M) and glybenclamide (an ATP-sensitive potassium channel inhibitor) (10(-5) M) did not alter the responses to ET-1. The endothelium-derived relaxing factor (EDRF) inhibitor N(w)-nitro-L-arginine (2 x 10(-4) M) not only inhibited the dilator response to ET-1 almost completely, but also potentiated the constrictor response. Finally, N(w)-nitro-L-arginine alone had a mild vasoconstrictor effect in newborn pig lung. The results of these studies indicate that ET-1 has both vasodilator and vasoconstrictor activity in neonatal pig pulmonary vascular bed. This vasodilator activity may be mediated by EDRF. Considering the potency of the constrictor effect of ET-1 in neonatal pig pulmonary circulation and the existence of a combined dilator response, ET-1 may play an important physiologic and pathophysiologic role in neonatal pulmonary circulation.