A long-acting prostacyclin agonist with thromboxane inhibitory activity for pulmonary hypertension.
BACKGROUND
The balance between prostacyclin and thromboxane plays an important role in the regulation of pulmonary vascular tone. Recently, we developed ONO-1301, a novel, long-acting prostacyclin agonist with thromboxane synthase inhibitory activity.


OBJECTIVE
We investigated whether modulation of prostacyclin/thromboxane balance by ONO-1301 ameliorates monocrotaline-induced pulmonary hypertension in rats.


METHODS
After subcutaneous injection of monocrotaline or vehicle, rats were randomized to receive repeated subcutaneous administration of ONO-1301 or vehicle twice per day for 3 wk.


RESULTS
There was significant development of pulmonary hypertension 3 wk after monocrotaline injection. Treatment with ONO-1301 significantly attenuated the increases in right ventricular systolic pressure and ratio of right ventricular weight to body weight in monocrotaline rats. Furthermore, ONO-1301 significantly attenuated the increase in medial wall thickness of peripheral pulmonary arteries in monocrotaline rats. The half-life of plasma ONO-1301 concentration after a single subcutaneous administration was approximately 5.6 h. A single administration of ONO-1301 increased plasma cyclic adenosine 3', 5'-monophosphate level, which lasted at least up to 8 h. Treatment with ONO-1301 significantly decreased plasma 11-dehydro-thromboxane B2, a metabolite of thromboxane, in monocrotaline rats. Finally, Kaplan-Meier survival curves demonstrated that repeated administration of ONO-1301 improved survival rate in monocrotaline rats compared with vehicle administration (80 vs. 30% in 6-wk survival).


CONCLUSIONS
Subcutaneous administration of a novel prostacyclin agonist (ONO-1301) markedly attenuated monocrotaline-induced pulmonary hypertension and improved survival in rats. The beneficial effects of ONO-1301 may occur through its long-lasting stimulation of cyclic adenosine 3', 5'-monophosphate and inhibition of thromboxane synthase.
Kataoka
Masaharu
M
Department of Regenerative Medicine and Tissue Engineering, National Cardiovascular Center Research Institute, 5-7-1 Fujishirodai, Suita, Osaka 565-8565, Japan.
Nagaya
Noritoshi
N
Satoh
Toru
T
Itoh
Takefumi
T
Murakami
Shinsuke
S
Iwase
Takashi
T
Miyahara
Yoshinori
Y
Kyotani
Shingo
S
Sakai
Yoshiki
Y
Kangawa
Kenji
K
Ogawa
Satoshi
S
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D011464:Epoprostenol / Q000031:analogs & derivatives; D006339:Heart Rate / Q000187:drug effects*; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000201:enzymology* / Q000503:physiopathology*; D007279:Injections, Subcutaneous; D008297:Male; D016686:Monocrotaline; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013929:Thromboxane B2 / Q000031:analogs & derivatives* / Q000097:blood; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors
D011725:Pyridines; C105488:ONO 1301; D013929:Thromboxane B2; C049235:11-dehydro-thromboxane B2; D016686:Monocrotaline; D011464:Epoprostenol; D013930:Thromboxane-A Synthase