Vol. 294, Issue 1, 45-51, July 2000

Effect of Allelic Polymorphism of the B₁ and B₂ Receptor Genes on the Contractile Responses of the Human Umbilical Vein to Kinins¹

Steeve Houle, Michelle Landry², Ritchie Audet³, Johanne Bouthillier, Dimcho R. Bachvarov⁴ and François Marceau

Centre Hospitalier Universitaire de Québec, Centre de recherche du Pavillon l'Hôtel-Dieu de Québec, Quebec, Canada

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 E_max 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; E_max 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 the B₁R 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 T allele 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 neighboring B₁R gene.