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Molecular Pharmacology

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Research ArticleArticle

A Kinetic Binding Study to Evaluate the Pharmacological Profile of a Specific Leukotriene C4 Binding Site Not Coupled to Contraction in Human Lung Parenchyma

Saula Ravasi, Valérie Capra, Maurizio Mezzetti, Simonetta Nicosia and G. Enrico Rovati
Molecular Pharmacology June 2000, 57 (6) 1182-1189;
Saula Ravasi
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Valérie Capra
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Maurizio Mezzetti
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Simonetta Nicosia
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G. Enrico Rovati
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Abstract

We report the identification of a novel pharmacological profile for the leukotriene (LT)C4 binding site we previously identified in human lung parenchyma (HLP). We used a series of classic cysteinyl-LT(CysLT)1 receptor antagonists belonging to different chemical classes and the dual CysLT1-CysLT2 antagonist BAY u9773 for both binding and functional studies. Because the presence of (S)-decyl-glutathione interfered with cysteinyl-LT binding, with a kinetic protocol we avoided the use of this compound. By means of heterologous dissociation time courses, we demonstrated that zafirlukast, iralukast, and BAY u9773 selectively competed only for 3H-LTD4 binding sites, whereas pobilukast, pranlukast, and CGP 57698 dissociated both3H-LTC4 and 3H-LTD4from their binding sites. Thus, with binding studies, we have been able to identify a pharmacological profile for LTC4 distinct from that of LTD4 receptor (CysLT1) in HLP. On the contrary, in functional studies, all of the classic antagonists tested were able to revert both LTC4- and LTD4-induced contractions of isolated HLP strips. Thus, LTD4 and LTC4 contract isolated HLP strips through the same CysLT1 receptor. The results of kinetic binding studies, coupled to a sophisticated data analysis, confirm our hypothesis that HLP membranes contain two cysteinyl-LT high-affinity binding sites with different pharmacological profiles. In functional studies, however, LTD4- and LTC4-induced contractions are mediated by the same CysLT1 receptor. In conclusion, the specific LTC4 high-affinity binding site cannot be classified as one of the officially recognized CysLT receptors, and it is not implicated in LTC4-induced HLP strip contractions.

Footnotes

  • Send reprint requests to: Dr. G. Enrico Rovati, Institute of Pharmacological Sciences, University of Milan, Via Balzaretti 9, 20133 Milan, Italy. E-mail:GEnrico.Rovati{at}unimi.it

  • Abbreviations:
    Cysteinyl-LT
    cysteine-containing leukotrienes
    LT
    leukotriene
    (S)-decyl-GSH
    (S)-decyl-glutathione
    PG
    prostaglandin
    HLP
    human lung parenchyma
    Gpp(NH)p
    guanosine-5′-(β,γ-imido)triphosphate
    • Received September 17, 1999.
    • Accepted February 17, 2000.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 57 (6)
Molecular Pharmacology
Vol. 57, Issue 6
1 Jun 2000
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Research ArticleArticle

A Kinetic Binding Study to Evaluate the Pharmacological Profile of a Specific Leukotriene C4 Binding Site Not Coupled to Contraction in Human Lung Parenchyma

Saula Ravasi, Valérie Capra, Maurizio Mezzetti, Simonetta Nicosia and G. Enrico Rovati
Molecular Pharmacology June 1, 2000, 57 (6) 1182-1189;

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Research ArticleArticle

A Kinetic Binding Study to Evaluate the Pharmacological Profile of a Specific Leukotriene C4 Binding Site Not Coupled to Contraction in Human Lung Parenchyma

Saula Ravasi, Valérie Capra, Maurizio Mezzetti, Simonetta Nicosia and G. Enrico Rovati
Molecular Pharmacology June 1, 2000, 57 (6) 1182-1189;
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