Abstract 1781 Poster Session I, Saturday, 5/1 (poster 105)
Background: In utero ligation of the ovine ductus arteriosus produces fetal and neonatal PH and alterations in the hemodynamic responses to nitric oxide (NO). The epoxyeicosatrienoic acids (EETs), cytochrome P450 metabolites of arachidonic acid, have been identified as potential "endothelial-derived hyperpolarizing factors" and have been demonstrated to mediate vasodilation in systemic vessels from several species. There are scant and conflicting data regarding the effect of EETs in the pulmonary circulation. Furthermore, the role of EETs in the modulation of vascular tone in the context of neonatal PH has not previously been investigated.
Hypotheses: (1) 11,12-EET causes vasodilation in term, fetal ovine PRV. (2) 11,12-EET-induced vasodilation in PRV is endothelial-independent. (3) PRV from newborn lambs with pulmonary hypertension have diminished dilator responses to 11,12-EET.
Methods: Fetal lambs underwent ductal ligation at 126 days gestational age and were delivered 9 days later. Isolated PRV from lambs with and without PH were cannulated and pressurized to 15 mm Hg for measurement of lumen diameter (LD) with a video dimension analyzer. PRV were preconstricted with 0.1 µM endothelin-1 and continuous LD measurements were recorded during cumulative administration of 11,12-EET (0.0001-10 µM). In some vessels, the endothelium was denuded by infusion of an air bolus to determine the endothelial-dependency of the dilator response.
Results: 11,12-EET caused a significant concentration-dependent dilation in ovine PRV. Removal of the endothelium had no effect on the dilator response of PRV to 11,12-EET. 11,12-EET was an equally effective dilator in PRV from lambs with and without PH. (0.1 µM 11,12-EET caused 61.6 + 7.2 % vs. 60.3 + 10 % dilation in PRV from control vs. ligated lambs, respectively; EC50 = 0.012 vs 0.013 µM in PRV from control and ligated lambs, respectively.)
Conclusion: 11,12-EET is a potent vasodilator in the pulmonary microcirculation of term fetal lambs. 11,12-EET mediates vasodilation by an endothelial-independent mechanism. The ability of the pulmonary microcirculation to dilate in response to 11,12-EET is preserved in a lamb ductal-ligation model of PH. We speculate that 11,12-EET mediates vasodilation by directly hyperpolarizing vascular smooth muscle. In contrast to the NO-cGMP pathway, the downstream signaling mechanisms mediating vasodilation to the EETs are intact in this model of fetal and neonatal PH, opening a new avenue for therapeutic intervention in neonates with Persistent Pulmonary Hypertension of the Newborn.