Abstract:
RATIONALE:Most patients with pulmonary arterial hypertension (PAH) die from right heart failure. Beta-adrenergic receptor blockade reduces mortality by about 30% in patients with left-sided systolic heart failure, but is not used in PAH. OBJECTIVES:To assess the effect of the adrenergic receptor blocker carvedilol on the pulmonary circulation and right heart in experimental pulmonary hypertension in rats. METHODS:Angioproliferative pulmonary hypertension was induced in rats by combined exposure to the vascular endothelial growth factor-receptor antagonist SU5416 and hypoxia. Carvedilol treatment was started after establishment of pulmonary hypertension and right heart dysfunction. MEASUREMENTS AND MAIN RESULTS:Compared with vehicle-treated animals, treatment with carvedilol resulted in increased exercise endurance; improved right ventricular (RV) function (increased tricuspid annular plane systolic excursion and decreased RV dilatation); and an increased cardiac output. The morphology of the pulmonary vessels and the RV afterload were not affected by carvedilol. Carvedilol treatment was associated with enhancement of RV fetal gene reactivation, increased protein kinase G (PKG) activity, and a reduction in capillary rarefaction and fibrosis. Metoprolol had similar but less pronounced effects in the SU5416 and hypoxia model. Cardioprotective effects were noted of both carvedilol and metoprolol in the monocrotaline model. In the case of carvedilol, but not metoprolol, part of these effects resulted from a prevention of monocrotaline-induced lung remodeling. CONCLUSIONS:Adrenergic receptor blockade reverses RV remodeling and improves RV function in experimental pulmonary hypertension. Beta-adrenergic receptor blockers are not recommended in humans with PAH before their safety and efficacy are assessed in well-designed clinical trials.
journal_name
Am J Respir Crit Care Medauthors
Bogaard HJ,Natarajan R,Mizuno S,Abbate A,Chang PJ,Chau VQ,Hoke NN,Kraskauskas D,Kasper M,Salloum FN,Voelkel NFdoi
10.1164/rccm.201003-0335OCsubject
Has Abstractpub_date
2010-09-01 00:00:00pages
652-60issue
5eissn
1073-449Xissn
1535-4970pii
201003-0335OCjournal_volume
182pub_type
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