Document Detail

Differential effects of Selexipag [corrected] and prostacyclin analogs in rat pulmonary artery.
MedLine Citation:
PMID:  22918043     Owner:  NLM     Status:  MEDLINE    
{4-[(5,6-Diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}acetic acid (ACT-333679) is the main metabolite of the selective prostacyclin (PGI(2)) receptor (IP receptor) agonist selexipag. The goal of this study was to determine the influence of IP receptor selectivity on the vasorelaxant efficacy of ACT-333679 and the PGI(2) analog treprostinil in pulmonary artery under conditions associated with pulmonary arterial hypertension (PAH). Selexipag and ACT-333679 evoked full relaxation of pulmonary artery from control and monocrotaline (MCT)-PAH rats, and ACT-333679 relaxed normal pulmonary artery contracted with either endothelin-1 (ET-1) or phenylephrine. In contrast, treprostinil evoked weaker relaxation than ACT-333679 of control pulmonary artery and failed to induce relaxation of pulmonary artery from MCT-PAH rats. Treprostinil did not evoke relaxation of normal pulmonary artery contracted with either ET-1 or phenylephrine. Expression of prostaglandin E(3) (EP(3)) receptor mRNA was increased in pulmonary artery from MCT-PAH rats. In contraction experiments, the selective EP(3) receptor agonist sulprostone evoked significantly greater contraction of pulmonary artery from MCT-PAH rats compared with control rats. The presence of a threshold concentration of ET-1 significantly augmented the contractile response to sulprostone in normal pulmonary artery. ACT-333679 did not evoke direct contraction of rat pulmonary artery, whereas treprostinil evoked concentration-dependent contraction that was inhibited by the EP(3) receptor antagonist (2E)-3-(3',4'-dichlorobiphenyl-2-yl)-N-(2-thienylsulfonyl)acrylamide. Antagonism of EP(3) receptors also revealed a relaxant response to treprostinil in normal pulmonary artery contracted with ET-1. These data demonstrate that the relaxant efficacy of the selective IP receptor agonist selexipag and its metabolite ACT-333679 is not modified under conditions associated with PAH, whereas relaxation to treprostinil may be limited in the presence of mediators of disease.
Keith Morrison; Rolf Studer; Roland Ernst; Franck Haag; Katalin Kauser; Martine Clozel
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Publication Detail:
Type:  In Vitro; Journal Article     Date:  2012-08-23
Journal Detail:
Title:  The Journal of pharmacology and experimental therapeutics     Volume:  343     ISSN:  1521-0103     ISO Abbreviation:  J. Pharmacol. Exp. Ther.     Publication Date:  2012 Dec 
Date Detail:
Created Date:  2012-11-15     Completed Date:  2013-01-24     Revised Date:  2013-02-11    
Medline Journal Info:
Nlm Unique ID:  0376362     Medline TA:  J Pharmacol Exp Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  547-55     Citation Subset:  IM    
Drug Discovery Department, Actelion Pharmaceuticals Ltd., Switzerland.
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MeSH Terms
Acetamides / pharmacology*
Acetates / pharmacology*
Alprostadil / analogs & derivatives,  metabolism
Disease Models, Animal
Dose-Response Relationship, Drug
Epoprostenol / analogs & derivatives*,  pharmacology
Hypertension, Pulmonary / metabolism,  physiopathology
Pulmonary Artery / drug effects*,  metabolism,  physiopathology
Pyrazines / pharmacology*
Rats, Wistar
Receptors, Epoprostenol / agonists
Vasoconstrictor Agents / pharmacology
Vasodilation / drug effects*
Vasodilator Agents / pharmacology*
Reg. No./Substance:
0/(4-((5,6-diphenylpyrazin-2-yl)(isopropyl)amino)butoxy)acetic acid; 0/2-(4-((5,6-diphenylpyrazin-2-yl)(isopropyl)amino)butoxy)-N-(methylsulfonyl)acetamide; 0/Acetamides; 0/Acetates; 0/Pyrazines; 0/Receptors, Epoprostenol; 0/Vasoconstrictor Agents; 0/Vasodilator Agents; 0/treprostinil; 35121-78-9/Epoprostenol; 745-65-3/Alprostadil; 802-31-3/prostaglandin E3
Erratum In:
J Pharmacol Exp Ther. 2013 Jan;344(1):317

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