Prolonged Estradiol Infusion Causes a Marked and Sustained Increase in Pulmonary Blood Flow in Fetal Lambs • 1717

Abstract

Estradiol (E2), a steroid hormone which causes vasodilation of many adult tissues, is present in high levels in the fetus and surges just prior to delivery. However, whether E2 contributes to the marked increase in pulmonary blood flow (PBF) which characterizes the normal transitional circulation at birth is not known. Because the surge in E2 immediately preceeds the fall in pulmonary vascular resistance (PVR), we hypothesized that E2 modulates the increase in PBF at birth. To study whether E2 causes pulmonary vasodilation in fetal lambs, we treated chronically prepared lambs with intrapulmonary infusions of E2 or vehicle (V) and measured their hemodynamic responses. Fetal surgery was performed at 128 d (term=147 d) and catheters were placed in the aorta, main pulmonary artery, and left atrium for pressure measurements and the left pulmonary artery (LPA) for local infusions of E2. An ultrasonic flow transducer was placed around the left pulmonary artery to measure blood flow. Aortic and pulmonary artery pressure (PAP), left atrial pressure (LAP), and left pulmonary blood flow (Qp) were measured daily. PVR in the left lung was calculated by (PAP-LAP)/Qp. After recovery from surgery, E2 (250 ng/hr; n=9) or vehicle (0.025% ethanol; n=4) was infused continuously into the LPA for 8 days or until PBF increased. E2 treatment increased left lung blood flow(195±44 vs. 55±12 ml/min, E2 vs. V, p<0.05) and decreased left lung PVR (0.31±0.07 vs. 0.93±0.20 mmHg/ml/min, E2 vs. V, p<0.05). The response of individual animals varied markedly and treated females responded earlier than did males (change in left lung PVR at 48 hours,-44±16 vs. 15±10%, female vs. male, p<0.05). In a second set of extremely premature animals (n=4), fetal surgery was performed at 114 d and E2 infusions started 3 d after surgery. 2 of these 4 animals responded, with PBF increasing from 53 and 73 to 186 and 173 ml/min, respectively. We conclude that continuous infusion of E2 causes marked and sustained pulmonary vasodilation in near-term fetal lambs, and that this effect can also be demonstrated in very premature fetal lambs. Because E2 causes acute nitric oxide (NO) release and endothelial nitric oxide synthase upregulation in isolated pulmonary artery endothelial cells from fetal lambs, we speculate that E2 mediates its vasoactive effects through endogenous NO release.