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Research ArticleCARDIOVASCULAR

Effect of Allelic Polymorphism of the B1 and B2 Receptor Genes on the Contractile Responses of the Human Umbilical Vein to Kinins

Steeve Houle, Michelle Landry, Ritchie Audet, Johanne Bouthillier, Dimcho R. Bachvarov and François Marceau
Journal of Pharmacology and Experimental Therapeutics July 2000, 294 (1) 45-51;
Steeve Houle
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Michelle Landry
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Ritchie Audet
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Johanne Bouthillier
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Dimcho R. Bachvarov
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François Marceau
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Abstract

The human genes corresponding to the two receptor (R) subtypes for bradykinin (BK)-related peptides, the B1R and B2R, are known to be polymorphic. The human isolated umbilical vein responds by contractions to stimulation by kinins via constitutive B2Rs and inducible B1Rs. Vascular rings from 100 different umbilical cords were submitted to a standardized protocol where Emax values were obtained at 2 and 6 h of incubation, and EC50 values were estimated at 6 h for the B1R agonist Sar-[d-Phe8]des-Arg9-BK;Emax and EC50 values were also obtained for the B2R agonist BK at 4 h. The genotype of each tissue donor was determined for two polymorphic sites in theB1R gene and three such sites in the B2R gene. The (−/−) genotype of a frequent insertion/deletion polymorphism of the B2R exon 1 was associated with increased contractile efficiency of the B1R agonist, Sar-[d-Phe8]des-Arg9-BK, but had no effect on BK-induced contractility. A B2R exon 2 polymorphism (C181 → T) selectively influenced the potency of BK (EC50 higher when the Tallele was present). The other polymorphisms studied were not found to affect kinin-induced contractility. Although most of the frequent polymorphic alleles of the kinin receptor genes are functionally neutral or determine functional alterations that are not detectable using the method used here, two B2R polymorphic sites (exon 1, exon 2) modestly influence function. As the exon 1 B2R polymorphism predicts the response of the B1R agonist, it may be in linkage disequilibrium with an unknown, functionally important polymorphism of the neighboringB1R gene.

Footnotes

  • Send reprint requests to: François Marceau, M.D., Ph.D., Professor, Centre Hospitalier Universitaire de Québec, Centre de recherche, Pavillon l'Hôtel-Dieu de Québec, 11 Côte-du-Palais, Québec (Québec) Canada G1R 2J6. E-mail: francois.marceau{at}crhdq.ulaval.ca

  • ↵1 This work was supported by Medical Research Council of Canada Grant MT-14077.

  • ↵2 Recipient of a studentship from the Medical Research Council of Canada.

  • ↵3 Present address: DiagnoCure Inc., 2050 René-Lévesque Ouest Blvd., Sainte-Foy (Québec), Canada G1V 2K8.

  • ↵4 Recipient of the Ernest J. B. Tomlinson Scholarship Award from the Kidney Foundation of Canada and of a Fonds de la Recherche en Santé du Québec Scholarship, successively.

  • Abbreviations:
    R
    receptor
    BK
    bradykinin
    5-HT
    5-hydroxytryptamine
    RFLP
    restriction fragment length polymorphism
    • Received May 6, 1999.
    • Accepted March 9, 2000.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 294 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 294, Issue 1
1 Jul 2000
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Research ArticleCARDIOVASCULAR

Effect of Allelic Polymorphism of the B1 and B2 Receptor Genes on the Contractile Responses of the Human Umbilical Vein to Kinins

Steeve Houle, Michelle Landry, Ritchie Audet, Johanne Bouthillier, Dimcho R. Bachvarov and François Marceau
Journal of Pharmacology and Experimental Therapeutics July 1, 2000, 294 (1) 45-51;

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Research ArticleCARDIOVASCULAR

Effect of Allelic Polymorphism of the B1 and B2 Receptor Genes on the Contractile Responses of the Human Umbilical Vein to Kinins

Steeve Houle, Michelle Landry, Ritchie Audet, Johanne Bouthillier, Dimcho R. Bachvarov and François Marceau
Journal of Pharmacology and Experimental Therapeutics July 1, 2000, 294 (1) 45-51;
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