Bosentan for the prevention of overcirculation-induced experimental pulmonary arterial hypertension.
BACKGROUND
The dual endothelin-receptor antagonist bosentan has been reported to improve pulmonary arterial hypertension, but the role of endothelins in the pathogenesis of the condition remains uncertain. We investigated the roles of endothelin-1 (ET-1), nitric oxide (NO), vascular endothelial growth factor (VEGF), and tenascin in overcirculation-induced pulmonary hypertension in piglets, as a model of early pulmonary arterial hypertension, with or without bosentan therapy.


RESULTS
Thirty 3-week-old piglets were randomized to placebo or to bosentan 15 mg/kg BID after the anastomosis of the left subclavian artery to the pulmonary arterial trunk or after a sham operation. Three months later, the animals underwent a hemodynamic evaluation followed by cardiac and pulmonary tissue sampling for morphometry, immunohistochemistry, and real-time quantitative PCR. Chronic systemic-to-pulmonary shunting increased circulating plasma ET-1, pulmonary mRNA for ET-1, ET(B) receptor, inducible NO synthase, VEGF, and pulmonary ET-1 and VEGF proteins. There were increases in myocardial mRNA for ET(A) receptor and VEGF and in myocardial VEGF protein. Pulmonary and myocardial tissue mRNA for tenascin did not change. Normalized-flow pulmonary artery pressure increased from 20 (2) to 33 (1) mm Hg [mean (SEM)], arteriolar medial thickness increased on average by 83%, and these changes were completely prevented by bosentan therapy. Right ventricular end-systolic elastance increased in proportion to pulmonary arterial elastance with or without bosentan.


CONCLUSIONS
Experimental overcirculation-induced pulmonary arterial hypertension appears to be causally related to an activation of the pulmonary ET-1 system and as such is completely prevented by the dual endothelin receptor antagonist bosentan.
Rondelet
Benoît
B
Laboratory of Physiology, Free University of Brussels, Brussels, Belgium.
Kerbaul
François
F
Motte
Sophie
S
van Beneden
Ronald
R
Remmelink
Myriam
M
Brimioulle
Serge
S
McEntee
Kathleen
K
Wauthy
Pierre
P
Salmon
Isabelle
I
Ketelslegers
Jean-Marie
JM
Naeije
Robert
R
D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D000077300:Bosentan; D016228:Endothelial Growth Factors / Q000096:biosynthesis / Q000235:genetics; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000096:biosynthesis / Q000235:genetics; D016232:Endothelins / Q000502:physiology; D006439:Hemodynamics; D006976:Hypertension, Pulmonary / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000235:genetics; D008168:Lung / Q000378:metabolism; D008222:Lymphokines / Q000096:biosynthesis / Q000235:genetics; D009206:Myocardium / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis / Q000235:genetics; D011651:Pulmonary Artery / Q000473:pathology / Q000601:surgery; D011652:Pulmonary Circulation; D012333:RNA, Messenger / Q000096:biosynthesis; D013449:Sulfonamides / Q000627:therapeutic use*; D013552:Swine; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D000959:Antihypertensive Agents; D016228:Endothelial Growth Factors; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D016232:Endothelins; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D012333:RNA, Messenger; D013449:Sulfonamides; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D009569:Nitric Oxide; D000077300:Bosentan