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

Abstract

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.

• Authors: Masaharu Kataoka, Noritoshi Nagaya, Toru Satoh, Takefumi Itoh, Shinsuke Murakami, Takashi Iwase, Yoshinori Miyahara, Shingo Kyotani, Yoshiki Sakai, Kenji Kangawa, Satoshi Ogawa
• Journal: American journal of respiratory and critical care medicine (Am J Respir Crit Care Med) Vol. 172 Issue 12 Pg. 1575-80 (Dec 15 2005) ISSN: 1073-449X [Print] United States
• PMID: 16192456 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

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