Pharmacology of the single isomer, esuberaprost (beraprost-314d) on pulmonary vascular tone, IP receptors and human smooth muscle proliferation in pulmonary hypertension.
Animals
Cell Proliferation
Cells, Cultured
Dose-Response Relationship, Drug
Epoprostenol
/ analogs & derivatives
Female
HEK293 Cells
Humans
Hypertension, Pulmonary
/ drug therapy
Muscle, Smooth, Vascular
/ drug effects
Myocytes, Smooth Muscle
/ drug effects
Rats
Rats, Sprague-Dawley
Receptors, Epoprostenol
/ agonists
Vasodilation
/ drug effects
Vasodilator Agents
/ chemistry
Beraprost optical isomers
Cyclic AMP
Prostanoid IP and EP(3) receptors
Pulmonary hypertension
Smooth muscle cell proliferation
Vascular tone
Journal
Biochemical pharmacology
ISSN: 1873-2968
Titre abrégé: Biochem Pharmacol
Pays: England
ID NLM: 0101032
Informations de publication
Date de publication:
08 2019
08 2019
Historique:
received:
12
01
2019
accepted:
29
05
2019
pubmed:
4
6
2019
medline:
31
3
2020
entrez:
4
6
2019
Statut:
ppublish
Résumé
Beraprost is a prostacyclin analogue and IP receptor agonist which is approved to treat pulmonary arterial hypertension (PAH) in Asia. The beraprost-314d isomer (esuberaprost) is one of four stereoisomers contained within the racemic mixture of beraprost. The pharmacological profile of esuberaprost is now evaluated to determine how stereoisomer separation affects its potency and mode of action in functional assays. Vascular tone was assessed using wire myography in rat and human distal pulmonary arteries (PAs) pre-contracted with U46619 (100 nM). HEK-293 cells stably expressing the human IP receptor (HEK-293-IP) and pulmonary arterial smooth muscle cells (PASMCs) derived from PAH patients were used to assess cyclic AMP (cAMP) generation and cell proliferation, respectively. Esuberaprost relaxed rat PAs with a 5-fold greater potency compared with beraprost, and effects were strongly inhibited by RO3244794 (IP receptor antagonist) or L-NAME (NO synthase inhibitor). Esuberaprost caused EP Stereoisomer separation of beraprost has a significant effect on the pharmacology of the individual isomer, esuberaprost, identified in vitro as a highly potent prostanoid IP receptor agonist.
Sections du résumé
BACKGROUND AND PURPOSE
Beraprost is a prostacyclin analogue and IP receptor agonist which is approved to treat pulmonary arterial hypertension (PAH) in Asia. The beraprost-314d isomer (esuberaprost) is one of four stereoisomers contained within the racemic mixture of beraprost. The pharmacological profile of esuberaprost is now evaluated to determine how stereoisomer separation affects its potency and mode of action in functional assays.
EXPERIMENTAL APPROACH
Vascular tone was assessed using wire myography in rat and human distal pulmonary arteries (PAs) pre-contracted with U46619 (100 nM). HEK-293 cells stably expressing the human IP receptor (HEK-293-IP) and pulmonary arterial smooth muscle cells (PASMCs) derived from PAH patients were used to assess cyclic AMP (cAMP) generation and cell proliferation, respectively.
KEY RESULTS
Esuberaprost relaxed rat PAs with a 5-fold greater potency compared with beraprost, and effects were strongly inhibited by RO3244794 (IP receptor antagonist) or L-NAME (NO synthase inhibitor). Esuberaprost caused EP
CONCLUSIONS AND IMPLICATIONS
Stereoisomer separation of beraprost has a significant effect on the pharmacology of the individual isomer, esuberaprost, identified in vitro as a highly potent prostanoid IP receptor agonist.
Identifiants
pubmed: 31158340
pii: S0006-2952(19)30214-X
doi: 10.1016/j.bcp.2019.05.026
pii:
doi:
Substances chimiques
Receptors, Epoprostenol
0
Vasodilator Agents
0
beraprost
35E3NJJ4O6
Epoprostenol
DCR9Z582X0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
242-252Informations de copyright
Copyright © 2019 Elsevier Inc. All rights reserved.