Endothelin B Receptor Blockade Attenuates Pulmonary Vasodilation in Oxygen-Ventilated Fetal Lambs

<i>Background:</i> Endothelin-1 (ET-1) contributes to the regulation of pulmonary vascular tone in the normal ovine fetus and in models of perinatal pulmonary hypertension. In the fetal lamb lung, the effects of ET-1 depend on the balance of at least two endothelin receptor subtypes: ET_A and ET_B. ET_A receptors are located on smooth muscle cells and mediate vasoconstriction and smooth muscle proliferation. Stimulation of endothelial ET_B receptors causes vasodilation through release of nitric oxide and also functions to remove ET-1 from the circulation. However, whether activation of ET_B receptors contributes to the fall in pulmonary vascular tone at birth is unknown. <i>Objective and Methods:</i> To determine the role of acute ET_B receptor blockade in pulmonary vasodilation in response to birth-related stimuli, we studied the hemodynamic effects of selective ET_B receptor blockade with BQ-788 during mechanical ventilation with low (<10%) and high FiO₂ (100%) in near-term fetal sheep. <i>Results:</i> Intrapulmonary infusion of BQ-788 did not change left pulmonary artery (LPA) blood flow and pulmonary vascular resistance (PVR) at baseline. In comparison with controls, BQ-788 treatment attenuated the rise in LPA flow with low and high FiO₂ ventilation (p < 0.001 vs. control for each FiO₂ concentration). PVR progressively decreased during mechanical ventilation with low and high FiO₂ in both groups, but PVR remained higher after BQ-788 treatment throughout the study period (p < 0.001). <i>Conclusions:</i> We conclude that selective ET_B receptor blockade attenuates pulmonary vasodilation at birth. We speculate that ET_B receptor stimulation contributes to pulmonary vasodilation at birth in the ovine fetus.