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

Abstract

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. (Circulation. 2003;107:1329-1335.)

Signaling Molecules in Overcirculation-Induced Pulmonary Hypertension in Piglets

“…The surgical procedure and postoperative care were performed as previously reported. Sildenafil was a gift from Pfizer, Inc. (Cambridge, Mass) 10 …”

“…10 Pulmonary vascular resistance (PVR) was partitioned into an arterial component (PVRa) and a venous component (PVRv) from the analysis of the Ppa decay curve after inflating the balloon of the pulmonary artery catheter. 10 PVR was defined by multipoint Ppa/Q plots obtained by rapid inflation of the inferior vena cava balloon.…”

“…10 Pulmonary vascular resistance (PVR) was partitioned into an arterial component (PVRa) and a venous component (PVRv) from the analysis of the Ppa decay curve after inflating the balloon of the pulmonary artery catheter. 10 PVR was defined by multipoint Ppa/Q plots obtained by rapid inflation of the inferior vena cava balloon. 10 Hemodynamic and blood gases measurements were obtained after ensuring steady-state conditions (stable HR, Psa, and Ppa) for 60 min, after shunt closure in the shunted animals.…”

“…10 Because lambs with overcirculation-induced pulmonary hypertension present with an increased expression of PDE-5 11 and angiotensin II might exert angiogenetic or antiangiogenetic effects, depending on the associated upregulation of its AT-1 or AT-2 receptors, 12,13 we specifically addressed the questions of whether angiopoietin-1/BMPR signaling is abnormal in this early PAH model and how this is related not only to the ET-1, iNOS, and VEGF systems, but also to the expressions of PDE-5 and of angiotensin II.…”

Endothelin: setting the scene in PAH

“…Bosentan is currently the only orally active dual ET receptor antagonist competitively antagonising the binding of ET-1 to both ETA and ETB. In all animal models of PAH, bosentan prevents and in some cases can reverse the development of PAH, vascular remodelling and right ventricular hypertrophy [20][21][22][23] and dual endothelin receptor antagonism has been shown to positively influence survival [18]. In the study by JASMIN et al [18], in an established model of PAH, selective (ETA) or dual ET receptor antagonists were administered 2 weeks after injection of saline or 60 mg?kg -1 monocrotaline (MCT).…”