A long-acting prostacyclin agonist with thromboxane inhibitory activity for pulmonary hypertension

Am J Respir Crit Care Med. 2005 Dec 15;172(12):1575-80. doi: 10.1164/rccm.200501-102OC. Epub 2005 Sep 28.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Pressure / drug effects*
  • Epoprostenol / analogs & derivatives
  • Heart Rate / drug effects*
  • Hypertension, Pulmonary / chemically induced
  • Hypertension, Pulmonary / enzymology*
  • Hypertension, Pulmonary / physiopathology*
  • Injections, Subcutaneous
  • Male
  • Monocrotaline
  • Pyridines / administration & dosage
  • Pyridines / pharmacology*
  • Rats
  • Rats, Wistar
  • Thromboxane B2 / analogs & derivatives*
  • Thromboxane B2 / blood
  • Thromboxane-A Synthase / antagonists & inhibitors


  • Pyridines
  • ONO 1301
  • Thromboxane B2
  • 11-dehydro-thromboxane B2
  • Monocrotaline
  • Epoprostenol
  • Thromboxane-A Synthase