Chronic Intrauterine Pulmonary Hypertension Alters Endothelin Receptor Activity in the Ovine Fetal Lung

Abstract

Although endothelin (ET) contributes to the regulation of pulmonary vascular tone in the normal fetus, little is known about its role in pulmonary hypertension in the perinatal period. To examine the role of the ETB receptor in the normal ovine fetal lung, we studied the hemodynamic effects of ET-3 (a selective ETB receptor agonist) before and after RES-701 (a selective ETB receptor antagonist). RES-701 (10 mu g/min for 10 min) did not change basal pulmonary tone and blocked pulmonary vasodilation to ET-3 (500 ng/min for 10 min). To examine the effects of experimental perinatal pulmonary hypertension on activity of the ETA and ETB receptors, we studied the hemodynamic effects of ET-3, ET-1 (a nonselective ETA and ETB receptor agonist), and BQ 123 (a selective ETA receptor antagonist) in 12 chronically prepared late gestation fetal lambs after partial ligation of the ductus arteriosus. Serial changes in the pulmonary vascular effects of these agents were measured early (1-3 d) and late (7-10 d) after partial ductus arteriosus ligation. Left lung total pulmonary resistance in the normal late-gestation fetus was 0.62 +/- 0.01 mm Hg/ml/min (n = 4). After partial ductus arteriosus ligation, total pulmonary resistance increased to 1.2 +/- 0.3 (early; p < 0.05 versus normal), and progressively rose to 1.9 +/- 0.2 mm Hg/ml/min (late; p < 0.05 versus early). Intrapulmonary infusion of ET-3 (500 ng/min for 10 min) increased pulmonary blood flow from 94 +/- 11 to 183 +/- 17 mL/min in the normal fetus, but had no effect during late pulmonary hypertension. Infusions of ET-1 (50 ng/min for 30 min) caused transient pulmonary vasodilation followed by vasoconstriction during early pulmonary hypertension. During late pulmonary hypertension, however, infusion of ET-1 caused predominantly vasoconstriction. Pulmonary vasodilation to BQ 123 (100 mu g/min for 10 min) was greater during late than early pulmonary hypertension (43 versus 21%; p < 0.05). After 10 d of ductus arteriosus ligation, immunoreactive ET-1 content in whole lung tissue was 3-fold higher in hypertensive (n = 7) than control (n = 10) lungs (p < 0.05). We conclude that the ETB receptor contributes little to regulation of basal vascular tone in the normal ovine fetal lung and that chronic intrauterine pulmonary hypertension causes the loss of ETB-mediated vasodilation, progressive ETA-mediated vasoconstriction, and increased lung ET-1 content. We speculate that diminished ETB receptor-mediated vasodilation in combination with enhanced ETA receptor-mediated vasoconstriction and increased ET-1 production contributes to high pulmonary vascular resistance in perinatal pulmonary hypertension.

TBC3711, an ETA Receptor Antagonist, Reduces Neonatal Hypoxia-Induced Pulmonary Hypertension in Piglets

“…Similar findings were reported in an ovine model of pulmonary hypertension (16) and in human neonates with pulmonary hypertension (14). This differs from our previous report (15), in which we did not find an increase in ET-1 circulating levels with hypoxia, although receptor studies suggested that ET-1 levels must be increased.…”

“…Supporting its role in the pathogenesis of PPHN, high circulating levels of ET-1 have been found in newborns with PPHN (14). Furthermore, it has been shown that pulmonary hypertension in neonatal animals is associated with a loss of ET B -mediated vasodilation, sustained ET Amediated vasoconstriction, and increased lung ET-1 content (15)(16)(17).…”

Prolonged endothelin A receptor blockade attenuates chronic pulmonary hypertension in the ovine fetus.

“…Ductus arteriosus ligation causes progressive pulmonary hypertension as previously shown (13). Mean MPA pressure in the normal fetus at this gestational age is 43 Ϯ 4 mmHg (13).…”

“…In the normal fetal lung, ET-1 is present, and contributes to high PVR (9)(10)(11)(12). We have previously shown that chronic intrauterine pulmonary hypertension causes the loss of ET Bmediated vasodilation, progressive ET A -mediated vasoconstriction, and increased lung ET-1 content (13). Little is known, however, about the role of ET-1 and its receptors in chronic pulmonary hypertension in the perinatal period.…”

“…The MPA catheter was inserted between the ductus arteriosus and the pulmonic valve. The ductus arteriosus was partially ligated using umbilical tape (13). The thoracotomy incision was closed in layers.…”