Human β2-adrenergic receptor gene haplotypes and venodilation in vivo

Background and Objective: beta(2)-Adrenergic receptors (beta(2)-ARs) are polymorphic. In vitro studies have shown that agonist-promoted down-regulation is enhanced for Arg16Gly and blunted for Gln27Glu beta(2)-AR variants; Thr164Ile beta(2)-ARs exhibit reduced responsiveness to agonist stimulation. Our objective was to determine whether beta(2)-AR polymorphisms affect beta(2)-AR-mediated venodilation in healthy subjects in vivo. Methods: We studied dilation of phenylephrine-preconstricted dorsal hand veins induced by terbutaline (50-1000 ng/min) using the Aellig hand vein technique in subjects homozygous for the 3 most common beta(2)-AR haplotypes (group A, Arg16Gln27Thr164 [wild type (WT)] [n = 10]; group B, Gly16Gln27Thr164 [n = 8]; and group C, Gly16Glu27Thr164 [n = 9]) and in 8 subjects heterozygous for Thr164Ile beta(2)-AR (group D) at baseline and after 2 weeks of treatment with oral terbutaline, 5 mg 3 times daily. Results. Terbutaline dose-dependently dilated hand veins; sensitivity to terbutaline was 2-fold higher in haplotype group A versus group B or C; maximal dilation, however, was not haplotype-dependent. In Thr164Ile subjects terbutaline sensitivity but not maximal dilation was 4-fold lower than in WT subjects. Long-term terbutaline treatment desensitized venous beta(2)-AR in a haplotype-dependent manner: The extent of desensitization (reduction in maximal venodilation) was largest for haplotype A, modest for haplotype B, and almost absent for haplotype C. Long-term terbutaline treatment also desensitized venous Thr164Ile beta(2)-AR; after terbutaline treatment, dose-response curves for terbutaline-induced venodilation were superimposable in WT and Thr164Ile beta(2)-AR subjects. Conclusion: beta(2)-AR-mediated dilation of human hand veins is influenced by the 3 most common beta(2)-AR haplotypes and blunted in subjects heterozygous for Thr164Ile beta(2)-AR. Long-term terbutaline treatment desensitizes venous beta(2)-AR in a haplotype-dependent manner, with haplotype A (Arg16Gln27Thr164) showing greater desensitization than haplotype B (Gly16Gln27Thr164), which shows greater desensitization than haplotype C (Gly16Glu27Thr164).