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Research ArticleCardiovascular

Identification of Contractile P2Y1, P2Y6, and P2Y12 Receptors in Rat Intrapulmonary Artery Using Selective Ligands

Callum Mitchell, Nawazish-i-Husain Syed, Asrin Tengah, Alison M. Gurney and Charles Kennedy
Journal of Pharmacology and Experimental Therapeutics December 2012, 343 (3) 755-762; DOI: https://doi.org/10.1124/jpet.112.198051
Callum Mitchell
Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, United Kingdom
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Nawazish-i-Husain Syed
Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, United Kingdom
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Asrin Tengah
Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, United Kingdom
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Alison M. Gurney
Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, United Kingdom
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Charles Kennedy
Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, United Kingdom
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Abstract

ATP and UDP constrict rat intrapulmonary arteries, but which receptors mediate these actions is unclear. Here, we used selective agonists and antagonists, along with measurements of P2Y receptor expression, to characterize the receptor subtypes involved. Isometric tension was recorded from endothelium-denuded rat intrapulmonary artery rings (i.d. 200–500 μm) mounted on a wire myograph. Expression of P2Y receptor subtype expression was determined by using reverse transcription-polymerase chain reaction with receptor-specific oligonucleotide primers. The selective P2Y1 agonist (N)-methanocarba-2-methylthioadenosine-5′-O-diphosphate (MRS2365) induced small, concentration-dependent contractions that were inhibited by the P2Y1 antagonist N6-methyl-2′-deoxyadenosine-3′,5′-bisphosphate (MRS2179). Contractions evoked by ATP were unaffected by MRS2179, but inhibited by approximately one-third by the P2Y12 antagonist N6-(2-methylthiomethyl)-2-(3,3,3-trifluoropropylthio)dichloro-methylene ATP (AR-C69931MX). Combined blockade of P2X1 and P2Y12 receptors virtually abolished the response to ATP. ADP also evoked contractions that were abolished by AR-C69931MX. The selective P2Y6 receptor agonist 3-(2-oxo-2-phenylethyl)-UDP (PSB 0474) evoked concentration-dependent contractions and was approximately three times more potent than UDP, but the P2Y14 agonist UDP-glucose had no effect. Contractions evoked by UDP were inhibited by the P2Y6 receptor antagonist N,N′-1,4-butanediylbis-N′-(3-isothiocyanatophenyl)thiourea (MRS2578), but not the cysteinyl leukotriene 1 (CysL1) antagonist 3-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)((3-dimethylamino-3-oxopropyl)thio)methyl)thiopropanoic acid (MK571). Higher concentrations of MRS2578 inhibited contractions to KCl, so they were not studied further. mRNA for P2Y1, P2Y6, and P2Y12 receptors was identified. Our working model is that P2Y12 and P2X1 receptors are present in rat intrapulmonary arteries and together mediate ATP-induced vasoconstriction. Contractile P2Y6, but not P2Y14 or CysLT1, receptors are also present and are a major site through which UDP evokes constriction.

Footnotes

  • C.M. and N.S. contributed equally to this study.

  • ↵1Current affiliation: University College of Pharmacy, University of the Punjab, Lahore, Pakistan.

  • ↵2Current affiliation: Pengiran Anak Puteri Rashidah Sa'adatul Bolkiah Institute of Health Sciences, University Brunei Darussalam, Brunei, Darussalam.

  • ↵3Current affiliation: Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom.

  • This study was supported by the British Heart Foundation [Grant FS/04/070] (to A.M.G. and C.K.).

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

    http://dx.doi.org/10.1124/jpet.112.198051.

  • ABBREVIATIONS:

    IPA
    intrapulmonary arteries
    MRS2365
    (N)-methanocarba-2-methylthioadenosine-5′-O-diphosphate
    MRS2179
    N6-methyl-2′-deoxyadenosine-3′,5′-bisphosphate
    AR-C69931MX
    N6-(2-methylthiomethyl)-2-(3,3,3-trifluoropropylthio)dichloro-methylene ATP
    PSB 0474
    3-(2-oxo-2-phenylethyl)-UDP
    MRS2578
    N,N′-1,4-butanediylbis-N′-(3-isothiocyanatophenyl)thiourea
    MK571
    3-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)((3-dimethylamino-3-oxopropyl)thio)methyl)thiopropanoic acid
    NF449
    4,4′,4′,4‴-[carbonylbis(imino-5,1,3-benzenetriyl-bis(carbonylimino))]tetrakis-1,3-benzenedisulfonic acid
    RT
    reverse transcription
    PCR
    polymerase chain reaction
    CysLT
    cysteinyl leukotrienes
    bp
    base pairs.

  • Received July 3, 2012.
  • Accepted September 17, 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 ArticleCardiovascular

P2Y Receptor-Mediated Pulmonary Artery Contraction

Callum Mitchell, Nawazish-i-Husain Syed, Asrin Tengah, Alison M. Gurney and Charles Kennedy
Journal of Pharmacology and Experimental Therapeutics December 1, 2012, 343 (3) 755-762; DOI: https://doi.org/10.1124/jpet.112.198051

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Research ArticleCardiovascular

P2Y Receptor-Mediated Pulmonary Artery Contraction

Callum Mitchell, Nawazish-i-Husain Syed, Asrin Tengah, Alison M. Gurney and Charles Kennedy
Journal of Pharmacology and Experimental Therapeutics December 1, 2012, 343 (3) 755-762; DOI: https://doi.org/10.1124/jpet.112.198051
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