PT  - JOURNAL ARTICLE
AU  - Stacy L. Porvasnik
AU  - Sean Germain
AU  - Jennifer Embury
AU  - Kimberley S. Gannon
AU  - Vincent Jacques
AU  - Justin Murray
AU  - Barry J. Byrne
AU  - Sharon Shacham
AU  - Faris Al-Mousily
TI  - PRX-08066, a Novel 5-Hydroxytryptamine Receptor 2B Antagonist, Reduces Monocrotaline-Induced Pulmonary Arterial Hypertension and Right Ventricular Hypertrophy in Rats
AID  - 10.1124/jpet.109.165001
DP  - 2010 Aug 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 364--372
VI  - 334
IP  - 2
4099  - http://jpet.aspetjournals.org/content/334/2/364.short
4100  - http://jpet.aspetjournals.org/content/334/2/364.full
SO  - J Pharmacol Exp Ther2010 Aug 01; 334
AB  - 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.