Urotensin-II Contributes to Pulmonary Vasoconstriction in a Perinatal Model of Persistent Pulmonary Hypertension of the Newborn Secondary to Meconium Aspiration Syndrome

Abstract

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...

Tracheal suctioning improves gas exchange but not hemodynamics in asphyxiated lambs with meconium aspiration

“…Oxygen saturations were monitored in the right foreleg using Masimo pulse oximeter (Rad 7, Masimo Corporation, Irvine, CA). These initial settings are similar to other studies in lambs with MAS ( 16 ). High PIP was required for the first few minutes to achieve adequate tidal volume (8-10ml/kg) and gradually correct PaCO 2 levels in asphyxiated lambs.…”

“…The majority of animal studies for meconium aspiration are conducted in postnatal (1-3 d old) piglets using human meconium instilled by positive pressure into an air-filled lung( 15 ). In the current model, meconium is aspirated by negative pressure before birth into a fluid-filled lung, similar to the human condition and is associated with HRF with an oxygenation index of 21.6 ± 4.7 in the no-suction group and 16.4 ± 3.7 in the suction group at 6 hours of age, similar to other lamb models of MAS( 16 ). A prior attempt to induce PPHN and HRF using a combination of asphyxia and meconium aspiration in preterm 160d gestation baboons (term ∼ 180d) was unsuccessful( 17 ) with concomitant asphyxia reducing the severity of MAS and PPHN.…”

Role of distinct phospholipases A2 and their modulators in meconium aspiration syndrome in human neonates

“…In the second work, piglets were studied for 12 h and indeed an sPLA2 increment was noticed only in the lung lobes selectively instilled with meconium [34]. Moreover, some animals had already negotiated a part of their perinatal transition, as they were more than 1 day old and this might be a main bias [37].…”

The Efficiency of a Urotensin II Antagonist in an Experimental Lung Fibrosis Model

“…Palosuran is a new potent and specific antagonist of the human U-II receptor (UT receptor) [12]. There are a limited number of studies focusing on palosuran and different U-II antagonists, which point out that U-II antagonists may lead to heart failure, cirrhosis, pulmonary HT, portal HT, and diabetic nephropathy [14,[27][28][29][30][31]. Bousette et al showed that the blockade of U-II led to a significant decrease in myocardial and endocardial fibrosis, as well as a reduction in collagen deposition [27].…”