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

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.