Modulating effect of a selective endothelin A receptor antagonist on pulmonary endothelin system protein expression in experimental diaphragmatic hernia.
OBJECTIVE
Previously, we reported that perinatal administration of atrasentan, a selective endothelin A receptor (ETA) 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.


METHODS
The effect of atrasentan on protein expression levels of ETs and ET receptors (ETA and ETB 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).


RESULTS
Right lung tissue of treated control lambs showed significantly higher ETA 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 ETA and ETB 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).


CONCLUSIONS
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.
Kavanagh
Mélanie
M
Pediatrics Research Unit, CHUL Research Center, CHUQ, Laval University, Sainte-Foy, QC, G1V 4G2, Canada.
Seaborn
Tommy
T
Crochetière
Josiane
J
Fournier
Louis
L
Battistini
Bruno
B
Piedboeuf
Bruno
B
Major
Diane
D
D000818:Animals; D000077868:Atrasentan; D065130:Endothelin A Receptor Antagonists; D020869:Gene Expression Profiling; D006439:Hemodynamics; D006548:Hernia, Diaphragmatic / Q000378:metabolism*; D007150:Immunohistochemistry; D008168:Lung / Q000378:metabolism; D009130:Muscle, Smooth / Q000378:metabolism; D011759:Pyrrolidines / Q000494:pharmacology*; D044022:Receptor, Endothelin A / Q000096:biosynthesis*; D044023:Receptor, Endothelin B / Q000096:biosynthesis*; D012119:Respiration; D012756:Sheep
D065130:Endothelin A Receptor Antagonists; D011759:Pyrrolidines; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D000077868:Atrasentan