Prolonged Endothelin B Receptor Blockade Causes Pulmonary Hypertension in the Ovine Fetus

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Abstract 135 Cardiology: Signaling Mechanisms and Cardiovascular Function Platform, Sunday, 5/2

Endothelin-1 (ET-1), a potent vasoactive and co-mitogenic peptide, contributes to the maintenance of high pulmonary vascular resistance (PVR) in the normal ovine fetus. The hemodynamic effects of ET-1 are due to activation of its receptors, ET-A or ET-B. In the ovine fetus, the ET-A receptor mediates vasoconstriction, and the ET-B receptor mediates vasodilation primarily through NO release. In other models, the ET-B receptor can also function as a clearance receptor for circulating ET-1. However, the physiologic importance of the ET-B receptor in the perinatal lung is incompletely understood. To examine the role of the ET-B receptor in regulation of vascular tone, we studied the hemodynamic effects of selective ET-B receptor blockade with BQ 788, in 7 fetal lambs (gestational age 131 days; 147 days = term). Catheters were placed in the main pulmonary artery (PAP, mmHg), aorta and left atrium (LAP, mmHg) to measure pressure, and in the left pulmonary artery (LPA) for selective left lung infusions. An ultrasonic flow transducer was placed around the LPA to measure blood flow (Qp, ml/min). PVR was calculated as PAP-LAP/Qp. Animals were treated with either BQ 788 (1 mg / day; n=3) or control (DMSO; n=4) by continuous infusion for 8 days in the LPA. Prolonged BQ 788 treatment in utero increased PAP from 39+/-2 to 59+/-3 mmHg (p<0.05) and PVR from 0.56+/-0.04 to 0.72+/-0.04 mmHg/ml/min (p<0.05). Vasodilation to the selective ET-B receptor agonist, SFX S6c, was attenuated after 8 days (- 52+/-12 vs -7+/-4 % fall in PVR, pre versus post BQ 788; p<0.05). After 8 days, animals were delivered by c-section, intubated and ventilated (Fi02 1.00). Mean PAP and PVR were higher in the animals treated with BQ 788 than controls (*=p<0.05 Control vs. BQ 788). (Table) We conclude that prolonged selective ET-B receptor blockade causes pulmonary hypertension in the ovine fetus and impairs the drop in PVR at birth. We speculate that chronic ET-B mediated vasodilation or ET-1 clearance is importance of fetal pulmonary tone and structure.

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