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- Title
Human β<sub>2</sub>-adrenergic receptor gene haplotypes and venodilation in vivo
- Authors
Bruck, Heike; Leineweber, Kirsten; Park, Jinny; Weber, Melanie; Heusch, Gerd; Philipp, Thomas; Brodde, Otto-Erich
- Abstract
Background and Objective: β2-Adrenergic receptors (β2-ARs) are polymorphic. In vitro studies have shown that agonist-promoted down-regulation is enhanced for Arg16Gly and blunted for Gln27Glu β2-AR variants; Thr164Ile β2-ARs exhibit reduced responsiveness to agonist stimulation. Our objective was to determine whether β2-AR polymorphisms affect β2-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 β2-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 β2-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 β2-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 β2-AR; after terbutaline treatment, dose-response curves for terbutaline-induced venodilation were superimposable in WT and Thr164Ile β2-AR subjects. Conclusion: β2-AR–mediated dilation of human hand veins is influenced by the 3 most common β2-AR haplotypes and blunted in subjects heterozygous for Thr164Ile β2-AR. Long-term terbutaline treatment desensitizes venous β2-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).
- Subjects
ADRENERGIC receptors; VEINS; BLOOD vessels; DRUG receptors
- Publication
Clinical Pharmacology & Therapeutics, 2005, Vol 78, Issue 3, p232
- ISSN
0009-9236
- Publication type
Article
- DOI
10.1016/j.clpt.2005.06.002