Effect of Allelic Polymorphism of the B1 and B2 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 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 B 1 R gene and three such sites in the B 2 R 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 B 1 R gene.