ENDOTHELIN-1 DOES NOT MEDIATE ACUTE HYPOXIC PULMONARY VASOCONSTRICTION IN THE INTACT NEWBORN LAMB

The mechanisms by which acute alveolar hypoxia induces pulmonary vasoconstriction remain unclear. Previous studies suggest that hypoxia-induced vasoconstriction is endothelium-dependent and is associated with the release of endothelin-I (ET-1), a potent vasoactive paracrine hormone produced by vascular endothelial cells. The vasoconstrictive effects of ET-1 are likely to be mediated by ET(A) receptors located on vascular smooth-muscle cells. BQ-123 is a selective ET(A) receptor antagonist. To determine the role of ET-1 and ET(A) receptors on resting tone and hypoxic pulmonary vasoconstriction, we studied the effects of ET-1 and BQ-123 at rest and during hypoxia-induced pulmonary vasoconstriction in 12 intact newborn lambs (<1 week old). At rest, the intrapulmonary infusion of BQ-123 did not change resting pulmonary arterial pressure but completely blocked the rapid increase in pulmonary artery pressure produced by high doses of ET-1 (2,000 ng/kg) (23.0 +/- 10.8% versus - 12.6 +/- 27.5%; p<0.05). During mechanical ventilation there was no difference in the increase in mean pulmonary arterial pressure and pulmonary vascular resistance induced by alveolar hypoxia before and after BQ-123 (34.0 +/- 8.9% versus 30.5 +/- 10.9% and 25.3 +/- 11.6% versus 35.2 +/- 22.4%). This study suggests that the pulmonary vasoconstrictive effects of ET-1 are mediated by ET(A) receptors and that ET-1 does not mediate acute hypoxic pulmonary vasoconstriction in intact newborn lambs.