title: A long-acting prostacyclin agonist with thromboxane inhibitory activity for pulmonary hypertension.
abstract: 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.
authors.affiliation: Department of Regenerative Medicine and Tissue Engineering, National Cardiovascular Center Research Institute, 5-7-1 Fujishirodai, Suita, Osaka 565-8565, Japan.
authors.forename: Masaharu
authors.initials: M
authors.lastname: Kataoka
authors.forename: Noritoshi
authors.initials: N
authors.lastname: Nagaya
authors.forename: Toru
authors.initials: T
authors.lastname: Satoh
authors.forename: Takefumi
authors.initials: T
authors.lastname: Itoh
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Murakami
authors.forename: Takashi
authors.initials: T
authors.lastname: Iwase
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Miyahara
authors.forename: Shingo
authors.initials: S
authors.lastname: Kyotani
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Sakai
authors.forename: Kenji
authors.initials: K
authors.lastname: Kangawa
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ogawa
mesh_terms: 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
chemical_list: D011725:Pyridines; C105488:ONO 1301; D013929:Thromboxane B2; C049235:11-dehydro-thromboxane B2; D016686:Monocrotaline; D011464:Epoprostenol; D013930:Thromboxane-A Synthase