Modulating effect of a selective endothelin A receptor antagonist on pulmonary endothelin system protein expression in experimental diaphragmatic hernia

• Published in: Journal of pediatric surgery 2005-09, Vol.40 (9), p.1382-1389
• Main Authors: Kavanagh, Mélanie, Seaborn, Tommy, Crochetière, Josiane, Fournier, Louis, Battistini, Bruno, Piedboeuf, Bruno, Major, Diane
• Format: Article
• Language: English
• Subjects: Animals; Endothelin A Receptor Antagonists; Gene Expression Profiling; Hemodynamics; Hernia, Diaphragmatic - metabolism; Immunohistochemistry; Lung - metabolism; Muscle, Smooth - metabolism; Pyrrolidines - pharmacology; Receptor, Endothelin A - biosynthesis; Receptor, Endothelin B - biosynthesis; Respiration; Sheep
• ISSN: 0022-3468; 1531-5037
• DOI: 10.1016/j.jpedsurg.2005.05.058

Previously, we reported that perinatal administration of atrasentan, a selective endothelin A receptor (ET A) antagonist, provided a beneficial effect on the cardiopulmonary profile under short-term conditions in newborn lambs with surgically induced congenital diaphragmatic hernia (CDH). We hypothesized that changes in the hemodynamic profile that we observed at birth in treated animals could be influenced by pulmonary modulation of the endothelin (ET) system. The effect of atrasentan on protein expression levels of ETs and ET receptors (ET A and ET B receptor) was investigated by immunohistochemistry in lung tissues of untreated control (n = 3), treated control (n = 6), untreated CDH (n = 6), and treated CDH newborn lambs (n = 8). Right lung tissue of treated control lambs showed significantly higher ET A protein expression levels in both vascular adventitia and airway epithelia when compared with that of untreated control lambs ( P < .05). In contrast, protein expression levels of ET A and ET B receptor were significantly lower in the vascular smooth muscle cells among other tissue subcompartments of the right lung of treated CDH newborn lambs vs CDH lambs ( P < .02 and P = .005, respectively). We speculate that rapid pulmonary modulation of ET system protein expression levels by atrasentan results from an indirect effect possibly dependent on ventilation and/or perfusion. In CDH groups, this could contribute to the beneficial effect of the treatment.