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.
Footnotes
This research was funded by EPIX Pharmaceuticals, the developer of PRX-08066.
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.109.165001.
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ABBREVIATIONS:
- PAH
- pulmonary arterial hypertension
- PRX-08066
- 5-((4-(6-chlorothieno[2,3-d]pyrimidin-4-ylamino)piperidin-1-yl)methyl)-2-fluorobenzonitrile monofumarate
- PH
- pulmonary hypertension
- 5-HT
- 5-hydroxytryptamine
- 5-HT2BR
- 5-HT receptor 2B
- AE
- alveolar edema
- AMI
- alveolar macrophage infiltration
- DF
- dexfenfluramine
- LV
- left ventricle
- LV+S
- LV + septum
- MCT
- monocrotaline
- OLP
- overall lung pathology
- PA
- pulmonary artery
- PAP
- peak pulmonary artery pressures
- PBS
- phosphate-buffered saline
- PE
- perivascular edema
- RV
- right ventricle
- ANOVA
- analysis of variance
- H&E
- hematoxylin-eosin
- VH
- vehicle
- MR
- magnetic resonance
- MRI
- MR imaging
- NS-304
- 2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}-N-(methylsulfonyl)acetamide
- RS-127445
- 4-(4-fluoro-1-naphthyl)-6-isopropylpyrimidin-2-amine
- PVR
- pulmonary vascular resistance.
- Received January 5, 2010.
- Accepted April 28, 2010.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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