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PRX-08066, a novel 5-hydroxytryptamine receptor 2B antagonist, reduces monocrotaline-induced pulmonary arterial hypertension and right ventricular hypertrophy in rats.
J Pharmacol Exp Ther. 2010 Aug; 334(2):364-72.JP

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+Show Affiliations

Department of Pediatrics, Powell Gene Therapy Center, University of Florida, Gainesville, Florida 32610-0266, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

20430844

Citation

Porvasnik, Stacy L., et al. "PRX-08066, a Novel 5-hydroxytryptamine Receptor 2B Antagonist, Reduces Monocrotaline-induced Pulmonary Arterial Hypertension and Right Ventricular Hypertrophy in Rats." The Journal of Pharmacology and Experimental Therapeutics, vol. 334, no. 2, 2010, pp. 364-72.
Porvasnik SL, Germain S, Embury J, et al. PRX-08066, a novel 5-hydroxytryptamine receptor 2B antagonist, reduces monocrotaline-induced pulmonary arterial hypertension and right ventricular hypertrophy in rats. J Pharmacol Exp Ther. 2010;334(2):364-72.
Porvasnik, S. L., Germain, S., Embury, J., Gannon, K. S., Jacques, V., Murray, J., Byrne, B. J., Shacham, S., & Al-Mousily, F. (2010). PRX-08066, a novel 5-hydroxytryptamine receptor 2B antagonist, reduces monocrotaline-induced pulmonary arterial hypertension and right ventricular hypertrophy in rats. The Journal of Pharmacology and Experimental Therapeutics, 334(2), 364-72. https://doi.org/10.1124/jpet.109.165001
Porvasnik SL, et al. PRX-08066, a Novel 5-hydroxytryptamine Receptor 2B Antagonist, Reduces Monocrotaline-induced Pulmonary Arterial Hypertension and Right Ventricular Hypertrophy in Rats. J Pharmacol Exp Ther. 2010;334(2):364-72. PubMed PMID: 20430844.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - PRX-08066, a novel 5-hydroxytryptamine receptor 2B antagonist, reduces monocrotaline-induced pulmonary arterial hypertension and right ventricular hypertrophy in rats. AU - Porvasnik,Stacy L, AU - Germain,Sean, AU - Embury,Jennifer, AU - Gannon,Kimberley S, AU - Jacques,Vincent, AU - Murray,Justin, AU - Byrne,Barry J, AU - Shacham,Sharon, AU - Al-Mousily,Faris, Y1 - 2010/04/29/ PY - 2010/5/1/entrez PY - 2010/5/1/pubmed PY - 2010/8/18/medline SP - 364 EP - 72 JF - The Journal of pharmacology and experimental therapeutics JO - J Pharmacol Exp Ther VL - 334 IS - 2 N2 - 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. SN - 1521-0103 UR - https://www.unboundmedicine.com/medline/citation/20430844/PRX_08066_a_novel_5_hydroxytryptamine_receptor_2B_antagonist_reduces_monocrotaline_induced_pulmonary_arterial_hypertension_and_right_ventricular_hypertrophy_in_rats_ L2 - https://jpet.aspetjournals.org/cgi/pmidlookup?view=long&amp;pmid=20430844 DB - PRIME DP - Unbound Medicine ER -