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(Circulation. 2003;107:1329.)
© 2003 American Heart Association, Inc.

Basic Science Reports

Bosentan for the Prevention of Overcirculation-Induced Experimental Pulmonary Arterial Hypertension

Benoît Rondelet, MD; François Kerbaul, MD; Sophie Motte, DVM; Ronald van Beneden, MSc; Myriam Remmelink, MD, PhD; Serge Brimioulle, MD, PhD; Kathleen McEntee, DVM, PhD; Pierre Wauthy, MD; Isabelle Salmon, MD, PhD; Jean-Marie Ketelslegers, MD, PhD; Robert Naeije, MD, PhD

From the Laboratory of Physiology, Free University of Brussels (B.R., F.K., S.M., S.B., K.M., P.W., R.N.), Unit of Diabetes and Nutrition, Catholic University of Louvain (R.v.B., J.-M.K.), and Department of Pathology, Erasmus University Hospital (M.R., I.S.), Brussels, Belgium.

Correspondence to Dr R. Naeije, Laboratory of Physiology, Free University Brussels, Erasmus Campus CP 604, Lennik Road 808, B-1070 Brussels. E-mail rnaeije{at}ulb.ac.be

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.

Methods and 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.

Key Words: endothelin • nitric oxide • growth substances • hypertension, pulmonary

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