Urotensin-II receptor blockade lowers pulmonary vascular resistance in a perinatal model of meconium aspiration syndrome

  • Dr Catherine Simpson, Murdoch Childrens Research Institute, Melbourne, Australia, Australia
  • A/Prof Joseph Smolich, Murdoch Childrens Research Institute, Melbourne, Australia, Australia
  • Dr Lara Shekerdemian, The Royal Children's Hopsital, Melbourne, Australia
  • Prof Daniel Penny, The Royal Children's Hopsital, Melbourne, Australia

    • OBJECTIVES:
    Endothelin-1 (ET-1) contributes to the pathogenesis of meconium aspiration syndrome (MAS), however, failure of ET-receptor antagonists to completely reverse associated haemodynamic abnormalities suggests a role for other vasoconstrictors. The potent vasoactive peptide urotensin-II (U-II), has been implicated in the pathophysiology of pulmonary hypertension, but its contribution to MAS is unknown. This study has determined the role of U-II in a perinatal model of MAS via measurement of circulating U-II and ET-1 levels, and U-II-receptor blockade studies.

    METHODS:
    After instrumentation with aortic, pulmonary trunk and left atrial catheters and pulmonary trunk/left pulmonary artery flow probes, 19 anaesthetized fetal lambs were randomised to the following groups: 1) control (n=5), 2) control plus specific U-II-receptor blockade with palosuran (10 mg/kg/hr infusion; n=5), 3) tracheal instillation of 20% human meconium (3 mL/kg; n=5), 4) meconium instillation plus palosuran (n=4). Haemodynamics and plasma U-II/ET-1 levels were measured for 6 hours after delivery during mechanical ventilation.

    RESULTS:
    After birth in control lambs, U-II levels increased (p<0.05), pulmonary vascular resistance (PVR) fell (p=0.01), and this fall was prevented by palosuran. By contrast, meconium animals displayed an exaggerated increase in U-II levels (p<0.05 vs control) with an elevation in PVR (p<0.005) which palosuran reduced by >50% (p<0.001). ET-1 levels rose in meconium (p<0.025) and meconium-palosuran (p<0.05) groups, but were not different between these groups.

    CONCLUSION:
    In a perinatal model of MAS, raised U-II levels in combination with a reduction in PVR by U-II-receptor blockade, suggest that U-II plays a major role in the pathophysiology of this condition.