TY - JOUR
T1 - A long-acting prostacyclin agonist with thromboxane inhibitory activity for pulmonary hypertension
AU - Kataoka, Masaharu
AU - Nagaya, Noritoshi
AU - Satoh, Toru
AU - Itoh, Takefumi
AU - Murakami, Shinsuke
AU - Iwase, Takashi
AU - Miyahara, Yoshinori
AU - Kyotani, Shingo
AU - Sakai, Yoshiki
AU - Kangawa, Kenji
AU - Ogawa, Satoshi
PY - 2005/12/15
Y1 - 2005/12/15
N2 - Rationale: 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. Objectives: 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. Measurements and Main 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.
AB - Rationale: 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. Objectives: 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. Measurements and Main 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.
KW - Hemodynamics
KW - Monocrotaline
KW - Vascular remodeling
KW - cAMP
UR - http://www.scopus.com/inward/record.url?scp=30444453849&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=30444453849&partnerID=8YFLogxK
U2 - 10.1164/rccm.200501-102OC
DO - 10.1164/rccm.200501-102OC
M3 - Article
C2 - 16192456
AN - SCOPUS:30444453849
VL - 172
SP - 1575
EP - 1580
JO - American Journal of Respiratory and Critical Care Medicine
JF - American Journal of Respiratory and Critical Care Medicine
SN - 1073-449X
IS - 12
ER -