title: 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 = 5), 2) control plus specific U-II receptor blockade with palosuran (n = 5), 3) tracheal instillation of meconium (n = 5), 4) meconium instillation plus palosuran (n = 4). Hemodynamics, PVR, and plasma U-II were measured for 6 h after delivery. After birth in controls, U-II increased (p < 0.05), and PVR fell (p = 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 < 0.05 versus control) with an increase in PVR (p < 0.005) that was attenuated by U-II receptor blockade (p < 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.
authors.affiliation: Heart Research Group, Murdoch Children's Research Institute, Parkville, Victoria 3052, Australia.
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Simpson
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Smolich
authors.forename: Lara S
authors.initials: LS
authors.lastname: Shekerdemian
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Penny
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001794:Blood Pressure; D002302:Cardiac Output; D004195:Disease Models, Animal; D019332:Endothelin-1 / Q000097:blood; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary / Q000097:blood / Q000209:etiology* / Q000503:physiopathology; D007231:Infant, Newborn; D008471:Meconium Aspiration Syndrome / Q000097:blood / Q000150:complications* / Q000503:physiopathology; D010100:Oxygen / Q000097:blood; D011651:Pulmonary Artery / Q000378:metabolism* / Q000503:physiopathology; D011804:Quinolines / Q000494:pharmacology; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000378:metabolism; D012756:Sheep; D013997:Time Factors; D015854:Up-Regulation; D014508:Urea / Q000031:analogs & derivatives / Q000494:pharmacology; D014579:Urotensins / Q000097:blood*; D014655:Vascular Resistance; D014661:Vasoconstriction; D014664:Vasodilation
chemical_list: D019332:Endothelin-1; D011804:Quinolines; D043562:Receptors, G-Protein-Coupled; D014579:Urotensins; D014508:Urea; C029677:urotensin II; D010100:Oxygen; C493249:1-(2-(4-benzyl-4-hydroxypiperidin-1-yl)ethyl)-3-(2-methylquinolin-4-yl)urea