Abstract 14695: Identification of Emetine as a Novel Therapeutic Agent for Pulmonary Hypertension in Rats -High-throughput Screening of 5,562 Compounds
Background: Pulmonary arterial hypertension (PAH) is characterized by enhanced proliferation and reduced apoptosis of pulmonary arterial smooth muscle cells (PASMCs). Emetine, a natural alkaloid extracted from Psychotria ipecacuanha, has been traditionally used to treat cough and amebiasis.
Methods and results: To discover a novel drug for PAH patients from the original library in Tohoku University (5,562 compounds), we performed high-throughput screening with PASMCs from PAH patients (PAH-PASMCs). In the first screening, we performed MTT assay for each compound (5 μmol/L) and found 80 compounds that effectively inhibited proliferation compared with controls (>20%). In the second screening, we performed the repeatability assay and the counter assay to exclude the compounds with cell toxicity. In the third screening, we performed a concentration-dependent assay and finally found that emetine inhibits PAH-PASMCs proliferation without any toxicity in normal PASMCs. Next, we performed functional tests for emetine in vivo. Six-week-old male SD rats were used for the two experimental PH models; monocrotaline-induced PH model and SU5416/hypoxia-induced PH model. In the prevention protocol, after subcutaneous injection of monocrotaline (60 mg/kg), the animals were assigned to the simultaneous treatment with either emetine (0.01 and 0.05 mg/kg/day) or vehicle in drinking water for 3 weeks. Emetine significantly reduced right ventricular (RV) systolic pressure (96±2 and 80±10 in the low- and high-dose group vs. 110±2 mmHg in the control group), RV hypertrophy (0.48±0.03 and 0.44±0.02 vs. 0.65±0.02), and PA remodeling compared with controls (all P<0.01, n=5). In the treatment protocol, after establishment of PH with SU5416 (20 mg/kg) and hypoxia (10% O2) for 3 weeks followed by normoxia for 6 weeks, the animals were randomized assigned to the treatment with emetine (0.05 mg/kg/day) or vehicle in drinking water for additional 4 weeks. Emetine significantly reduced RV systolic pressure (95±5 vs. 61±6 mmHg), RV hypertrophy (0.49±0.06 vs. 0.34±0.04), and PA remodeling compared with controls (all P<0.01, n=6~9).
Conclusions: By using high-throughput screening, we identified that emetine is a novel promising drug for the treatment of PAH.
Author Disclosures: M. Siddique: None. K. Satoh: None. R. Kurosawa: None. M. Al-Mamun: None. N. Kikuchi: None. J. Omura: None. T. Satoh: None. M. Nogi: None. S. Sunamura: None. H. Shimokawa: Speakers Bureau; Modest; Daiichi-Sankyo, Bayer Yakuhin.
- © 2016 by American Heart Association, Inc.