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

Abstract

Background: 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. Objective and Methods: 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. Results: 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). Conclusions: 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.

Urotensin-II Contributes to Pulmonary Vasoconstriction in a Perinatal Model of Persistent Pulmonary Hypertension of the Newborn Secondary to Meconium Aspiration Syndrome

“…Like U-II, ET-1 produces both endothelium-dependent vasodilation and endotheliumindependent vasoconstriction (11,30) and plasma ET-1 levels are increased in the perinatal transitional circulation in some species (31). Although controversial, some investigators have proposed that ET-1-mediated vasodilation contributes to the changes in PVR during the early neonatal period (31).…”

“…Po 2 was slightly lower during the study period in this group than controls. We consider that this is unlikely to contribute to the blunted pulmonary vasodilator response, for a number of reasons: first, the differences were modest, Sao 2 was well maintained; and second, in related models of the perinatal transitional circulation, neonatal pulmonary vasodilator responses occurred in the presence of much more extreme levels of hypoxemia (30,32). Consideration also needs to be given to whether the differences in pH between control and palosuran animals contributed to the blunted response.…”

Effects of Antenatal Glucocorticoids on Circulatory Adaptation at Birth in the Ovine Fetus

“…Otherwise, mechanical ventilation is also known to cause a large release of catecholamines and especially norepinephrine [11] . Interestingly, Smolich and coworkers reported that the lungs contribute about twofi fths of the total body norepinephrine spillover into the circulation [12,13] . Norepinephine is a potent pulmonary vasodilatator during perinatal life [3] .…”

“…Thus, the antenatal GC-enhanced response to alveolar ventilation could be partly related to the effects of antenatal GC on the lung vascular response to norepinephrine. Alternatively, other mediators are involved in the pulmonary vascular response to alveolar ventilation, including prostacyclin [14] or endothelin [13] . However, whether antenatal GC alter prostacyclin or endothelin production at birth is presently unknown.…”

Interaction of KATP Channels and Endothelin-1 in Lambs With Persistent Pulmonary Hypertension of the Newborn

“…ET receptors are also present in other structures within the lung, such as fibroblasts, bronchial smooth muscle, and epithelial cells, but their respective distribution remains unknown (6). The pulmonary vasoconstrictor effect of ET-1 results mainly from activation of the ET-A receptor, whereas activation of the endothelial ET-B receptor has been shown to induce relaxation (5,7). Plasma levels and expression of ET-1 are increased in models of pulmonary hypertension as well as in children with PPHN (8 -10).…”