Endothelin B receptor blockade attenuates pulmonary vasodilation in oxygen-ventilated fetal lambs.
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: ETA and ETB. ETA receptors are located on smooth muscle cells and mediate vasoconstriction and smooth muscle proliferation. Stimulation of endothelial ETB receptors causes vasodilation through release of nitric oxide and also functions to remove ET-1 from the circulation. However, whether activation of ETB receptors contributes to the fall in pulmonary vascular tone at birth is unknown.


OBJECTIVE
To determine the role of acute ETB receptor blockade in pulmonary vasodilation in response to birth-related stimuli, we studied the hemodynamic effects of selective ETB 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 ETB receptor blockade attenuates pulmonary vasodilation at birth. We speculate that ETB receptor stimulation contributes to pulmonary vasodilation at birth in the ovine fetus.
Ivy
D Dunbar
DD
Pediatric Heart Lung Center, Section of Cardiology, University of Colorado School of Medicine and The Children's Hospital, Denver, CO 80218, USA. dunbar.ivy@uchsc.edu
Lee
Dong-Seok
DS
Rairigh
Robyn L
RL
Parker
Thomas A
TA
Abman
Steven H
SH
D000818:Animals; D000831:Animals, Newborn; D001783:Blood Flow Velocity; D001794:Blood Pressure; D065131:Endothelin B Receptor Antagonists; D005333:Fetus / Q000098:blood supply; D005865:Gestational Age; D008168:Lung / Q000098:blood supply*; D009842:Oligopeptides / Q000494:pharmacology; D010100:Oxygen / Q000008:administration & dosage*; D036801:Parturition; D010880:Piperidines / Q000494:pharmacology; D011651:Pulmonary Artery / Q000502:physiology; D044023:Receptor, Endothelin B / Q000502:physiology; D012756:Sheep; D014655:Vascular Resistance; D014664:Vasodilation
D065131:Endothelin B Receptor Antagonists; D009842:Oligopeptides; D010880:Piperidines; D044023:Receptor, Endothelin B; C086539:BQ 788; D010100:Oxygen