Therapeutic efficacy of azaindole-1 in experimental pulmonary hypertension.
An accumulating body of evidence incriminates Rho kinase (ROCK) in the pathogenesis of pulmonary hypertension (PH). The therapeutic efficacy of azaindole-1, a novel highly selective and orally active ROCK inhibitor, has not yet been investigated in PH. This study aimed to investigate the effects of azaindole-1 on 1) acute hypoxic pulmonary vasoconstriction (HPV), 2) proliferation of pulmonary arterial smooth muscle cells (PASMCs) and 3) animal models of PH. Azaindole-1 significantly inhibited HPV in isolated, ventilated and buffer-perfused murine lungs and proliferation of primary rat PASMCs in vitro. Azaindole-1 was administered orally from 21 to 35 days after monocrotaline (MCT) injection in rats and hypoxic exposure in mice. Azaindole-1 (10 and 30 mg per kg body weight per day in rats and mice, respectively) significantly improved haemodynamics and right ventricular hypertrophy. Moreover, the medial wall thickness and muscularisation of peripheral pulmonary arteries were ameliorated. Azaindole-1 treatment resulted in a decreased immunoreactivity for phospho-myosin phosphatase target subunit 1 and proliferating cell nuclear antigen in pulmonary vessels of MCT-injected rats, suggesting an impaired ROCK activity and reduced proliferating cells. Azaindole-1 provided therapeutic benefit in experimental PH, and this may be attributable to its potent vasorelaxant and antiproliferative effects. Azaindole-1 may offer a useful approach for treatment of PH.
University of Giessen Lung Center, Giessen, Germany.
B K
BK
Dahal
D
D
Kosanovic
P K
PK
Pamarthi
A
A
Sydykov
Y-J
YJ
Lai
R
R
Kast
H
H
Schirok
J-P
JP
Stasch
H A
HA
Ghofrani
N
N
Weissmann
F
F
Grimminger
W
W
Seeger
R T
RT
Schermuly
D000818:Animals; D053961:Azabicyclo Compounds / Q000627:therapeutic use*; D049109:Cell Proliferation; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006439:Hemodynamics; D006976:Hypertension, Pulmonary / Q000188:drug therapy*; D007211:Indoles / Q000627:therapeutic use*; D008168:Lung / Q000473:pathology; D008297:Male; D051379:Mice; D051381:Rats; D017207:Rats, Sprague-Dawley; D013686:Telemetry / Q000379:methods; D013778:Tetrazolium Salts / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D013936:Thymidine / Q000737:chemistry; D016896:Treatment Outcome; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors
D053961:Azabicyclo Compounds; D004791:Enzyme Inhibitors; D007211:Indoles; D013778:Tetrazolium Salts; D013844:Thiazoles; C030374:indole; D054460:rho-Associated Kinases; C022616:thiazolyl blue; D013936:Thymidine