Endothelin A receptor blockade improves regression of flow-induced pulmonary vasculopathy in piglets.
OBJECTIVE
In patients with chronic thromboembolic pulmonary hypertension, high flow in unobstructed lung regions may induce small-vessel damage responsible for persistent pulmonary hypertension after pulmonary thromboendarterectomy. In piglets, closure of an experimental aortopulmonary shunt reverses the flow-induced vascular lesions and diminishes the elevated levels of messenger RNA (mRNA) expression for endothelin-1 and endothelin receptor A (ETA). We wanted to study the effect of the ETA antagonist TBC 3711 on reversal of flow-induced pulmonary vascular lesions.


METHODS
Twenty piglets were studied. In 15 piglets, pulmonary vasculopathy was induced by creating an aortopulmonary shunt. After 5 weeks of shunting, some animals were studied (n = 5); others underwent shunt closure for 1 week with (n = 5) or without (n = 5) TBC3711 treatment. Anti-ETA treatment started 1 week before and ended 1 week after the shunt closure. The controls were sham-operated animals (n = 5).


RESULTS
High blood flow led to medial hypertrophy of the distal pulmonary arteries (54.9% +/- 1.3% vs 35.3% +/- 0.9%; P < .0001) by stimulating smooth muscle cell proliferation (proliferating cell nuclear antigen) and increased the expression of endothelin-1, ETA or endothelin receptor type A or endothelin receptor A, angiopoietin 1, and Tie2 (real-time polymerase chain reaction). One week after shunt closure, gene expression levels were normal and smooth muscle cells showed increased apoptosis (terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling) without proliferation. However, pulmonary artery wall thickness returned to control values only in the group given TBC3711 (33.2% +/- 8% with and 50.3% +/- 1.3% without; P < .05).


CONCLUSIONS
Anti-ETA therapy accelerated the reversal of flow-induced pulmonary arterial disease after flow correction. In patients with chronic thromboembolic pulmonary hypertension and severe distal pulmonary vasculopathy, anti-ETA agents may prove useful for preventing persistent pulmonary hypertension after pulmonary thromboendarterectomy.
Mercier
Olaf
O
Inserm U999, Université Paris XI, Hôpital Marie Lannelongue, Le Plessis-Robinson, France. o.mercier@ccml.fr
Sage
Edouard
E
Izziki
Mohammed
M
Humbert
Marc
M
Dartevelle
Philippe
P
Eddahibi
Saadia
S
Fadel
Elie
E
D042683:Angiopoietin-1 / Q000235:genetics; D000818:Animals; D000831:Animals, Newborn; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001011:Aorta / Q000503:physiopathology / Q000601:surgery; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation; D004195:Disease Models, Animal; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1 / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D006984:Hypertrophy; D007555:Isoxazoles / Q000494:pharmacology*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D011651:Pulmonary Artery / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000601:surgery; D011652:Pulmonary Circulation / Q000187:drug effects*; D011655:Pulmonary Embolism / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D012333:RNA, Messenger / Q000378:metabolism; D044022:Receptor, Endothelin A / Q000235:genetics / Q000378:metabolism; D042787:Receptor, TIE-2 / Q000235:genetics; D013450:Sulfones / Q000494:pharmacology*; D013552:Swine; D013997:Time Factors
D042683:Angiopoietin-1; D000959:Antihypertensive Agents; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1; D007555:Isoxazoles; C485107:N-(2-acetyl-4,6-dimethylphenyl)-3-(3,4-dimethylisoxazol-5-ylsulfamoyl)thiophene-2-carboxamide; D012333:RNA, Messenger; D044022:Receptor, Endothelin A; D013450:Sulfones; D042787:Receptor, TIE-2