Evaluation of the effects of RP5063, a novel, multimodal, serotonin receptor modulator, as single-agent therapy and co-administrated with sildenafil, bosentan, and treprostinil in a monocrotaline-induced pulmonary arterial hypertension rat model.

Abstract

Pulmonary arterial hypertension (PAH), a condition that is defined by pulmonary vasculature constriction and remodeling, involves dysfunctional signaling of the serotonin (5-HT) receptors, 5-HT2A/2B/7. In a rat model of monocrotaline (MCT)-induced PAH, the effectiveness of RP5063 (RP), a dopamine and 5-HT receptor modulator, was evaluated as monotherapy and as an adjunct to standard PAH treatments. After a single 60 mg/kg dose of MCT, rats received vehicle (MCT+Veh; gavage twice-daily [b.i.d.]), RP (10 mg/kg; gavage b.i.d.), bosentan (B; 100 mg/kg; gavage BID), sildenafil (S; 50 mg/kg; gavage, BID), treprostinil (T; 100 ng/kg/min over 24 h intravenous), RP+B, RP+S, and RP+T for 28 days. Single-agent RP limited the functional and structural effects of PAH seen in the MCT+Veh group, with significant improvements in pulmonary hemodynamics, right ventricular (RV) hypertrophy, SO2, and pulmonary blood vessel structural changes. These effects appeared comparable with those associated with B, S, and T. Adjunctive RP treatment resulted in significantly lower mean pulmonary arterial pressures, RV systolic pressure. It also improved SO2 measurements, as compared with MCT+Veh (P < 0.05), and diastolic pulmonary artery pressure (P < 0.05), as compared with single-agent B and S therapy (Bonferroni method adjusting for multiplicity). RP+S appeared to show the most consistent and extensive effects on pulmonary hemodynamics, respiratory parameters, and histopathologic changes. These results corroborate earlier preclinical findings supporting the efficacy of single-agent RP in PAH. RP, as mono and adjunctive therapy compared with induced-control, mitigated the functional and structural effects of MCT-induced PAH.

• Authors: Laxminarayan Bhat, Jon Hawkinson, Marc Cantillon, Dasharatha G Reddy, Seema R Bhat, Charles-E Laurent, Annie Bouchard, Marzena Biernat, Dany Salvail
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 827 Pg. 159-166 (May 15 2018) ISSN: 1879-0712 [Electronic] Netherlands
• PMID: 29453947 (Publication Type: Journal Article)
• Copyright: Copyright © 2018 The Author(s). Published by Elsevier B.V. All rights reserved.

Chemical References

• Organic Chemicals
• RP5063
• Receptors, Serotonin
• Sulfonamides
• Monocrotaline
• Sildenafil Citrate
• Epoprostenol
• Bosentan
• treprostinil

Topics

• Animals
• Bosentan
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Drug Interactions
• Epoprostenol (administration & dosage, analogs & derivatives, pharmacology, therapeutic use)
• Hemodynamics (drug effects)
• Hypertension, Pulmonary (chemically induced, drug therapy, physiopathology)
• Male
• Monocrotaline (adverse effects)
• Organic Chemicals (adverse effects, pharmacology, therapeutic use)
• Pulmonary Artery (drug effects)
• Rats
• Rats, Wistar
• Receptors, Serotonin (metabolism)
• Sildenafil Citrate (administration & dosage, pharmacology, therapeutic use)
• Sulfonamides (administration & dosage, pharmacology, therapeutic use)