Effect of allelic polymorphism of the B(1) and B(2) receptor genes on the contractile responses of the human umbilical vein to kinins.
The human genes corresponding to the two receptor (R) subtypes for bradykinin (BK)-related peptides, the B(1)R and B(2)R, are known to be polymorphic. The human isolated umbilical vein responds by contractions to stimulation by kinins via constitutive B(2)Rs and inducible B(1)Rs. 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 EC(50) values were estimated at 6 h for the B(1)R agonist Sar-¿D-Phe(8)des-Arg(9)-BK; E(max) and EC(50) values were also obtained for the B(2)R agonist BK at 4 h. The genotype of each tissue donor was determined for two polymorphic sites in the B(1)R gene and three such sites in the B(2)R gene. The (-/-) genotype of a frequent insertion/deletion polymorphism of the B(2)R exon 1 was associated with increased contractile efficiency of the B(1)R agonist, Sar-¿D-Phe(8)des-Arg(9)-BK, but had no effect on BK-induced contractility. A B(2)R exon 2 polymorphism (C(181) --> T) selectively influenced the potency of BK (EC(50) 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 B(2)R polymorphic sites (exon 1, exon 2) modestly influence function. As the exon 1 B(2)R polymorphism predicts the response of the B(1)R agonist, it may be in linkage disequilibrium with an unknown, functionally important polymorphism of the neighboring B(1)R gene.
Houle
S
S
Centre Hospitalier Universitaire de Qu¿ebec, Centre de recherche du Pavillon l'H¿otel-Dieu de Qu¿ebec, Qu¿ebec, Canada.
Landry
M
M
Audet
R
R
Bouthillier
J
J
Bachvarov
D R
DR
Marceau
F
F
D000483:Alleles; D001920:Bradykinin / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D011110:Polymorphism, Genetic; D043783:Receptor, Bradykinin B1; D043782:Receptor, Bradykinin B2; D018002:Receptors, Bradykinin / Q000235:genetics*; D012701:Serotonin / Q000494:pharmacology; D014471:Umbilical Veins / Q000187:drug effects* / Q000502:physiology; D014661:Vasoconstriction / Q000187:drug effects*
D043783:Receptor, Bradykinin B1; D043782:Receptor, Bradykinin B2; D018002:Receptors, Bradykinin; D012701:Serotonin; D001920:Bradykinin