Human β 2 ‐adrenergic receptor gene haplotypes and venodilation in vivo

Background and Objective β 2 ‐Adrenergic receptors (β 2 ‐ARs) are polymorphic. In vitro studies have shown that agonist‐promoted down‐regulation is enhanced for Arg16Gly and blunted for Gln27Glu β 2 ‐AR variants; Thr164Ile β 2 ‐ARs exhibit reduced responsiveness to agonist stimulation. Our objective was to determine whether β 2 ‐AR polymorphisms affect β 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 β 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 β 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 β 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 β 2 ‐AR; after terbutaline treatment, dose‐response curves for terbutaline‐induced venodilation were superimposable in WT and Thr164Ile β 2 ‐AR subjects. Conclusion β 2 ‐AR‐mediated dilation of human hand veins is influenced by the 3 most common β 2 ‐AR haplotypes and blunted in subjects heterozygous for Thr164Ile β 2 ‐AR. Long‐term terbutaline treatment desensitizes venous β 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). Clinical Pharmacology & Therapeutics (2005) 78 , 232–238; doi: 10.1016/j.clpt.2005.06.002