Abstract 1906 Poster Session I, Saturday, 5/1 (poster 82)

Endothelin-1, a potent bronchoconstrictor and vasoactive substance, initiates its biological effects by binding to ETA and/or ETB receptors. The role of endothelin-1 as both a marker and mediator of pulmonary injury and inflammation is undefined currently in neonatal pulmonary disorders. We have found that, compared to 14 day old piglets exposed to 5 days of FiO2 ≥.96, similar aged piglets exposed to the combination of FiO2 ≥.96 + 45 ppm of inhaled NO for 5 days demonstrate elevated levels of immunoreactive endothelin-1 in lung lavage fluid obtained at sacrifice (80 ± 35) vs (20 ± 10) pg/ET-1/lung lavage (p < .02). We therefore investigated the effect of a specific and long acting endothelin receptor-A antagonist (TBC11521), (Texas Biotechnology Corporation, Houston, Tx), at 25 mg/kg intramuscularly q 12 hr to 6 14 day old piglets concomitantly exposed to O2 + NO for 5 days. Compared to 8 historical control and 2 concurrently exposed control animals receiving O2 and nitric oxide, the ETA receptor antagonist-treated animals demonstrated decreased lung wet weight at the time of sacrifice: 82.8 ± .79% versus 85.7 ± 1.95, x ± sd, p < .005. At the time of sacrifice, using an arbitrary score for clinical respiratory distress, a trend was noted in improved clinical outcome: 5 of the 6 TBC treated animals had a score of 0 or 1 versus 3 out of 10 of the O2 + NO treated animals alone (p < .1, Fishers Exact Test). To investigate whether endothelin alters lung water balance directly by influencing the activity of the regulatory epithelial cell enzyme, Na-K-ATPase, we performed an in vitro study assessing enzyme activity. Endothelin-1 was added to the reaction in concentrations from 0 to 10-7 M. There was no difference in activity, expressed as uM inorganic P/hr/mg protein among the assay with 0 or any of the ET-1 concentrations from 10-12 to 10-7 M. We conclude that the increased concentration of lung lavage ET-1 during NO + O2 exposure may contribute to extravascular pulmonary fluid accumulation by mechanisms other than a direct effect on Na-K ATPase. Our preliminary data suggest that by blocking the endothelin-A receptor during exposure, improvement in lung fluid balance and possibly in severity of respiratory distress can be induced in a neonatal lung injury model.