The effect of common polymorphisms of the beta2-adrenergic receptor on agonist-mediated vascular desensitization.
BACKGROUND
With continuous exposure to beta2-adrenergic agonists, vascular tissue becomes desensitized to agonist-mediated vasodilatation. We studied the effects of two common polymorphisms of the beta2-adrenergic receptor, one at codon 16 and one at codon 27, on agonist-mediated vasodilatation and desensitization in the vascular bed.


METHODS
We studied 26 healthy subjects who were selected to represent three genotypes: 7 were homozygous for the alleles encoding Arg16 and Gln27, 8 were homozygous for the alleles encoding Gly16 and Gln27, and 11 were homozygous for the alleles encoding Gly16 and Glu27. Vascular responses were assessed by measuring changes in the diameter of a dorsal hand vein. A dose-response curve of the effect of the beta2-adrenergic-receptor agonist isoproterenol was constructed (dose range, 4 to 480 ng per minute). Desensitization was then induced by a 2-hour continuous infusion of isoproterenol, and venodilatation was measured 30, 60, 90, and 120 minutes after the start of the infusion.


RESULTS
Subjects who were homozygous for Arg16 had almost complete desensitization; venodilatation in response to isoproterenol in this group decreased from a mean (+/-SE) of 44+/-11 percent to 8+/-4 percent (P=0.006). In contrast, subjects who were homozygous for Gly16 did not have significant desensitization, irrespective of the amino acid encoded by codon 27. Subjects who were homozygous for Glu27 had higher maximal venodilatation in response to isoproterenol than those who were homozygous for Gln27 (86+/-13 percent vs. 54+/-8 percent, P=0.03).


CONCLUSIONS
The Arg16 polymorphism of the beta2-adrenergic receptor is associated with enhanced agonist-mediated desensitization in the vasculature, and the Glu27 polymorphism is associated with increased agonist-mediated responsiveness. Therefore, polymorphisms of the beta2-adrenergic receptor are potentially important determinants of the vascular response to stress.
Dishy
V
V
Division of Clinical Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232-6602, USA.
Sofowora
G G
GG
Xie
H G
HG
Kim
R B
RB
Byrne
D W
DW
Stein
C M
CM
Wood
A J
AJ
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000328:Adult; D001794:Blood Pressure / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D005838:Genotype; D006801:Humans; D007545:Isoproterenol / Q000494:pharmacology*; D008297:Male; D010656:Phenylephrine / Q000494:pharmacology; D011110:Polymorphism, Genetic; D018343:Receptors, Adrenergic, beta-2 / Q000187:drug effects / Q000235:genetics*; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects* / Q000235:genetics*
D000316:Adrenergic alpha-Agonists; D000318:Adrenergic beta-Agonists; D018343:Receptors, Adrenergic, beta-2; D014662:Vasoconstrictor Agents; D010656:Phenylephrine; D007545:Isoproterenol