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Research ArticleDrug Discovery and Translational Medicine

Differential Effects of Selexipag and Prostacyclin Analogs in Rat Pulmonary Artery

Keith Morrison, Rolf Studer, Roland Ernst, Franck Haag, Katalin Kauser and Martine Clozel
Journal of Pharmacology and Experimental Therapeutics December 2012, 343 (3) 547-555; DOI: https://doi.org/10.1124/jpet.112.197152
Keith Morrison
Drug Discovery Department, Actelion Pharmaceuticals Ltd, Allschwil, Switzerland
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Rolf Studer
Drug Discovery Department, Actelion Pharmaceuticals Ltd, Allschwil, Switzerland
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Roland Ernst
Drug Discovery Department, Actelion Pharmaceuticals Ltd, Allschwil, Switzerland
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Franck Haag
Drug Discovery Department, Actelion Pharmaceuticals Ltd, Allschwil, Switzerland
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Katalin Kauser
Drug Discovery Department, Actelion Pharmaceuticals Ltd, Allschwil, Switzerland
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Martine Clozel
Drug Discovery Department, Actelion Pharmaceuticals Ltd, Allschwil, Switzerland
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Abstract

{4-[(5,6-Diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}acetic acid (ACT-333679) is the main metabolite of the selective prostacyclin (PGI2) 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 PGI2 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 E3 (EP3) receptor mRNA was increased in pulmonary artery from MCT-PAH rats. In contraction experiments, the selective EP3 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 EP3 receptor antagonist (2E)-3-(3′,4′-dichlorobiphenyl-2-yl)-N-(2-thienylsulfonyl)acrylamide. Antagonism of EP3 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.

Footnotes

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

    http://dx.doi.org/10.1124/jpet.112.197152.

  • ABBREVIATIONS:

    PGI2
    prostacyclin
    IP receptor
    PGI2 receptor
    EP1 receptor
    prostaglandin E receptor 1
    EP3 receptor
    prostaglandin E receptor 3
    DP1 receptor
    prostaglandin D2 receptor 1
    TP receptor
    thromboxane A2 receptor
    EPA
    extralobar pulmonary artery
    ET-1
    endothelin-1
    IPA
    intralobar pulmonary artery
    MCT
    monocrotaline
    PAH
    pulmonary arterial hypertension
    PGF2α
    prostaglandin F2α
    ACT-333679
    {4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}acetic acid
    DBTSA
    (2E)-3-(3′,4′-dichlorobiphenyl-2-yl)-N-(2-thienylsulfonyl)acrylamide
    SC51322
    8-chloro-2-[3-[(2-furanylmethyl)thio]-1-oxopropyl]hydrazide, dibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid
    GR32191B
    (4Z)-7-[(1R,2R,3S,5S)-5-([1,1′-biphenyl]-4-ylmethoxy)-3-hydroxy-2-(1-piperidinyl)cyclopentyl]-4-heptenoic acid
    U46619
    9,11-dideoxy-9α,11α-methanoepoxy prostaglandin F2α.

  • Received June 4, 2012.
  • Accepted August 22, 2012.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 343 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 343, Issue 3
1 Dec 2012
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Research ArticleDrug Discovery and Translational Medicine

Selexipag and Rat Pulmonary Artery

Keith Morrison, Rolf Studer, Roland Ernst, Franck Haag, Katalin Kauser and Martine Clozel
Journal of Pharmacology and Experimental Therapeutics December 1, 2012, 343 (3) 547-555; DOI: https://doi.org/10.1124/jpet.112.197152

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Research ArticleDrug Discovery and Translational Medicine

Selexipag and Rat Pulmonary Artery

Keith Morrison, Rolf Studer, Roland Ernst, Franck Haag, Katalin Kauser and Martine Clozel
Journal of Pharmacology and Experimental Therapeutics December 1, 2012, 343 (3) 547-555; DOI: https://doi.org/10.1124/jpet.112.197152
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