Meconium aspiration syndrome (MAS) disrupts perinatal decreases in pulmonary vascular resistance (PVR) and is the commonest cause of neonatal pulmonary hypertension. The contribution of the potent vasoactive agent urotensin-II (U-II), in the pathophysiology of this condition, is unknown. In a new perinatal model of MAS, we combined measurement of circulating U-II levels with U-II receptor blockade studies. Nineteen anesthetized lambs were instrumented then randomly allocated to the following groups: 1) control (n ϭ 5), 2) control plus specific U-II receptor blockade with palosuran (n ϭ 5), 3) tracheal instillation of meconium (n ϭ 5), 4) meconium instillation plus palosuran (n ϭ 4). Hemodynamics, PVR, and plasma U-II were measured for 6 h after delivery. After birth in controls, U-II increased (p Ͻ 0.05), and PVR fell (p ϭ 0.01) and this fall was prevented by U-II receptor blockade. By contrast, meconium lambs displayed a greater rise in U-II levels (p Ͻ 0.05 versus control) with an increase in PVR (p Ͻ 0.005) that was attenuated by U-II receptor blockade (p Ͻ 0.001). These findings suggest that U-II normally acts as a pulmonary vasodilator after birth, but in the presence of MAS, it assumes a vasoconstrictor role. U-II receptor blockade also improves pulmonary hemodynamics in this model. (Pediatr Res 67: 150-157, 2010) M econium aspiration syndrome (MAS) is a severe neonatal respiratory disorder (1) and is the commonest cause of pulmonary hypertension of the newborn (PHN) (2). MAS disrupts the perinatal transition in the pulmonary circulation, so that, the usual fall in pulmonary artery pressure (P PA ) and pulmonary vascular resistance (PVR), and increase in pulmonary artery blood flow (Q PA ) are impeded. These abnormalities, in association with damage to lung parenchyma induced by aspirated meconium, may lead to critical hypoxemia and pulmonary hypertension (1-4).Important knowledge regarding the pathophysiology of MAS has been obtained from animal models (1-4). However, a significant limitation of most existing models is that they have been performed in animals that are several days to weeks old and have already negotiated much of the perinatal transition. This limits the investigation of fundamental early events in the pathophysiology of MAS.Animal studies (5,6), which are consistent with observations in humans (6), indicate that the fall in PVR after birth is dependent on the action of endothelium-related vasoregulators. An imbalance in these vasoregulators is a characteristic feature of PHN, with up-regulation of vasoconstrictor influences (6). The vasoconstrictor that has received greatest attention in MAS is endothelin-1 (ET-1). Circulating ET-1 levels parallel the rise in P PA (7) and PVR (7) and antagonism of the ET receptor lowers these variables (2,8). However, as the hemodynamic abnormalities in MAS are not completely reversed by high doses of ET-receptor antagonists (2), it is clear that ET-1 is only one of a number of mediators in the pathophysiology of PHN in this setting.A recently u...