Urotensin-II contributes to pulmonary vasoconstriction in a perinatal model of persistent pulmonary hypertension of the newborn secondary to meconium aspiration syndrome.
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.
Simpson
Catherine M
CM
Heart Research Group, Murdoch Children's Research Institute, Parkville, Victoria 3052, Australia.
Smolich
Joseph J
JJ
Shekerdemian
Lara S
LS
Penny
Daniel J
DJ
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
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