Adrenergic receptor blockade reverses right heart remodeling and dysfunction in pulmonary hypertensive rats.
BACKGROUND
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.


OBJECTIVE
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.


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.
Director of the Victoria Johnson Center for Obstructive Lung Disease Research, Virginia Commonwealth University, 1220 East Broad Street, Richmond, VA 23298, USA.
Harm J
HJ
Bogaard
Ramesh
R
Natarajan
Shiro
S
Mizuno
Antonio
A
Abbate
Philip J
PJ
Chang
Vinh Q
VQ
Chau
Nicholas N
NN
Hoke
Donatas
D
Kraskauskas
Michael
M
Kasper
Fadi N
FN
Salloum
Norbert F
NF
Voelkel
D018674:Adrenergic Antagonists / Q000494:pharmacology*; D000818:Animals; D002227:Carbazoles / Q000494:pharmacology*; D000077261:Carvedilol; D004195:Disease Models, Animal; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000188:drug therapy*; D007211:Indoles / Q000008:administration & dosage; D008297:Male; D011412:Propanolamines / Q000494:pharmacology*; D011652:Pulmonary Circulation / Q000187:drug effects; D011758:Pyrroles / Q000008:administration & dosage; D051381:Rats; D017207:Rats, Sprague-Dawley; D042461:Vascular Endothelial Growth Factor A / Q000008:administration & dosage / Q000037:antagonists & inhibitors; D018497:Ventricular Dysfunction, Right / Q000139:chemically induced / Q000188:drug therapy*; D020257:Ventricular Remodeling / Q000187:drug effects*
D018674:Adrenergic Antagonists; D002227:Carbazoles; D007211:Indoles; D011412:Propanolamines; D011758:Pyrroles; D042461:Vascular Endothelial Growth Factor A; D000077261:Carvedilol; C116890:Semaxinib