Partial reversal of experimental pulmonary hypertension by phosphodiesterase-3/4 inhibition.
Phosphodiesterase (PDE) inhibitors are currently under investigation for the therapy of pulmonary hypertension. The present study was designed to investigate chronic effects of oral pumafentrine, a mixed selective PDE-3/4 inhibitor, in monocrotaline (MCT)-induced pulmonary hypertension in rats. Treatment with pumafentrine (10 mg.kg(-1) daily) from week 4 to 6 after a single injection of MCT (60 mg.kg(-1)) partially reversed pulmonary hypertension and right heart hypertrophy in rats. In addition, small pulmonary arterial muscularisation, media hypertrophy and decrease in lumen area were largely reversed. Inhibition of smooth muscle proliferation under pumafentrine was demonstrated in vivo as was a pro-apoptotic effect of pumafentrine on vascular cells. Moreover, pumafentrine dose-dependently increased cyclic adenosine monophosphate levels and inhibited proliferation of cultured pulmonary arterial smooth muscle cells. In conclusion, oral pumafentrine partially reverses monocrotaline-induced pulmonary hypertension, lung vascular remodelling and right heart hypertrophy in rats.
Dony
E
E
University of Giessen Lung Centre (UGLC), Klinikstrasse 36, 35392 Giessen, Germany.
Lai
Y-J
YJ
Dumitrascu
R
R
Pullamsetti
S S
SS
Savai
R
R
Ghofrani
H A
HA
Weissmann
N
N
Schudt
C
C
Flockerzi
D
D
Seeger
W
W
Grimminger
F
F
Schermuly
R T
RT
D000818:Animals; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3 / Q000187:drug effects; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000187:drug effects; D004195:Disease Models, Animal; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D017380:Hypertrophy, Right Ventricular / Q000139:chemically induced / Q000188:drug therapy*; D008168:Lung / Q000187:drug effects* / Q000473:pathology; D008297:Male; D016686:Monocrotaline / Q000008:administration & dosage; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects*; D009287:Naphthyridines / Q000494:pharmacology*; D058987:Phosphodiesterase 3 Inhibitors; D058988:Phosphodiesterase 4 Inhibitors; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D051381:Rats
D009287:Naphthyridines; D058987:Phosphodiesterase 3 Inhibitors; D058988:Phosphodiesterase 4 Inhibitors; D010726:Phosphodiesterase Inhibitors; C528394:pumafentrine; D016686:Monocrotaline; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4