PRX-08066, a novel 5-hydroxytryptamine receptor 2B antagonist, reduces monocrotaline-induced pulmonary arterial hypertension and right ventricular hypertrophy in rats.

Abstract

Pulmonary arterial hypertension (PAH) is a life-threatening disease that results in right ventricular failure. 5-((4-(6-Chlorothieno[2,3-d]pyrimidin-4-ylamino)piperidin-1-yl)methyl)-2-fluorobenzonitrile monofumarate (PRX-08066) is a selective 5-hydroxytryptamine receptor 2B (5-HT2BR) antagonist that causes selective vasodilation of pulmonary arteries. In the current study, the effects of PRX-08066 were assessed by using the monocrotaline (MCT)-induced PAH rat model. Male rats received 40 mg/kg MCT or phosphate-buffered saline and were treated orally twice a day with vehicle or 50 or 100 mg/kg PRX-08066 for 5 weeks. Pulmonary and cardiac functions were evaluated by hemodynamics, heart weight, magnetic resonance imaging (MRI), pulmonary artery (PA) morphology, and histology. Cardiac MRI demonstrated that PRX-08066 (100 mg/kg) significantly (P < 0.05) improved right ventricular ejection fraction. PRX-08066 significantly reduced peak PA pressure at 50 and 100 mg/kg (P < 0.05 and < 0.01, respectively) compared with MCT control animals. PRX-08066 therapy also significantly reduced right ventricle (RV)/body weight and RV/left ventricle + septum (P < 0.01 and < 0.001, respectively) compared with MCT-treated animals. Morphometric assessment of pulmonary arterioles revealed a significant reduction in medial wall thickening and lumen occlusion associated with both doses of PRX-08066 (P < 0.01). The 5-HT2BR antagonist PRX-08066 significantly attenuated the elevation in PA pressure and RV hypertrophy and maintained cardiac function. Pulmonary vascular remodeling was also diminished compared with MCT control rats. PRX-08066 prevents the severity of PAH in the MCT rat model.

• Authors: Stacy L Porvasnik, Sean Germain, Jennifer Embury, Kimberley S Gannon, Vincent Jacques, Justin Murray, Barry J Byrne, Sharon Shacham, Faris Al-Mousily
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 334 Issue 2 Pg. 364-72 (Aug 2010) ISSN: 1521-0103 [Electronic] United States
• PMID: 20430844 (Publication Type: Journal Article)

Chemical References

• 5-((4-(6-chlorothieno(2,3-d)pyrimidin-4-ylamino)piperidin-1-yl)methyl)-2-fluorobenzonitrile
• Pyrimidines
• Serotonin 5-HT2 Receptor Antagonists
• Thiophenes
• Monocrotaline

Topics

• Animals
• Hemodynamics (drug effects)
• Hypertension, Pulmonary (chemically induced, drug therapy, physiopathology)
• Hypertrophy, Right Ventricular (chemically induced, drug therapy, physiopathology)
• Magnetic Resonance Imaging
• Male
• Monocrotaline
• Myocardium (pathology)
• Organ Size
• Pulmonary Artery (drug effects, pathology, physiopathology)
• Pyrimidines (blood, therapeutic use)
• Rats
• Rats, Sprague-Dawley
• Serotonin 5-HT2 Receptor Antagonists
• Thiophenes (blood, therapeutic use)