. Nitric oxideendothelin-1 interactions after acute ductal constriction in fetal lambs. Am J Physiol Heart Circ Physiol 282: H862-H871, 2002. First published November 15, 2001 10.1152/ajpheart.00417.2001.-Acute partial compression of the fetal ductus arteriosus (DA) results in an initial increase in pulmonary blood flow (PBF) that is followed by acute vasoconstriction. The objective of the present study was to determine the role of nitric oxide (NO)-endothelin-1 (ET-1) interactions in the acute changes in pulmonary vascular tone after in utero partial constriction of the DA. Twelve lategestation fetal lambs (132-140 days) were instrumented to measure vascular pressures and left PBF. After a 24-h recovery period, acute constriction of the DA was performed by partially inflating a vascular occluder, and the hemodynamic variables were observed for 4 h. In control lambs (n ϭ 7), acute ductal constriction initially increased PBF by 627% (P Ͻ 0.05). However, this was followed by active vasoconstriction, such that PBF was restored to preconstriction values by 4 h. This was associated with a 43% decrease in total NO synthase (NOS) activity (P Ͻ 0.05) and a 106% increase in plasma ET-1 levels (P Ͻ 0.05). Western blot analysis demonstrated no changes in lung tissue endothelial NOS, preproET-1, endothelin-converting enzyme-1, or ETB receptor protein levels. The infusion of PD-156707 (an ETA receptor antagonist, n ϭ 5) completely blocked the vasoconstriction and preserved NOS activity. These data suggest that the fetal pulmonary vasoconstriction after acute constriction of the DA is mediated by NO-ET-1 interactions. These include an increase in ETA receptor-mediated vasoconstriction and an ETA receptor-mediated decrease in NOS activity. The mechanisms of these NO-ET-1 interactions, and their role in mediating acute changes in PBF, warrant further studies. ductus arteriosus; pulmonary circulation INCREASES in fetal pulmonary arterial pressure induced by mechanical constriction of the ductus arteriosus induce an acute increase in pulmonary blood flow that is followed by active vasoconstriction (1). This so-called "myogenic response," which returns pulmonary blood flow to preconstriction values within 2-4 h, may represent an adaptive response of the fetal pulmonary vasculature to maintain the normal low flow (44). However, chronic ductal constriction results in pulmonary vascular remodeling and many of the pathophysiological features of persistent pulmonary hypertension of the newborn (3,29,49). In fact, fetal ductal constriction secondary to maternal indomethacin use has been associated with persistent pulmonary hypertension of the newborn (45).Previous studies have demonstrated that vasoactive factors produced by the vascular endothelium, such as nitric oxide (NO) and endothelin-1 (ET-1), are important mediators of the fetal and transitional pulmonary circulations (11). NO is produced from its precursor, L-arginine, after the activation of endothelial NO synthase (eNOS) (31). Once released, NO diffuses into the smooth muscl...

Inhaled nitric oxide produces potent pulmonary vasodilation by activating soluble guanylate cyclase and increasing smooth muscle cell concentrations of guanosine-3',5'-cyclic monophosphate. However, alterations in endogenous nitric oxide/guanosine-3',5'-cyclic monophosphate during inhaled nitric oxide have been implicated in the clinically significant increases in pulmonary vascular resistance noted upon its acute withdrawal. Previous in vitro data suggest that exogenous nitric oxide/guanosine-3',5'-cyclic monophosphate can also alter cyclic adenosine monophosphate concentrations via their effect on cyclic adenosine monophosphate production and metabolism. The current in vivo study demonstrates that lung tissue cyclic adenosine monophosphate concentrations are decreased during inhaled nitric oxide and suggests a role for decreased cyclic adenosine monophosphate in the rebound pulmonary hypertension noted upon inhaled nitric oxide withdrawal. Milrinone may be a useful adjunct therapy during inhaled nitric oxide to preserve cyclic adenosine monophosphate concentrations and prevent rebound pulmonary hypertension.