Human beta2-adrenergic receptor gene haplotypes and venodilation in vivo.
OBJECTIVE
beta2-Adrenergic receptors (beta2-ARs) are polymorphic. In vitro studies have shown that agonist-promoted down-regulation is enhanced for Arg16Gly and blunted for Gln27Glu beta2-AR variants; Thr164Ile beta2-ARs exhibit reduced responsiveness to agonist stimulation. Our objective was to determine whether beta2-AR polymorphisms affect beta2-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 beta2-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 beta2-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 beta2-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 beta2-AR; after terbutaline treatment, dose-response curves for terbutaline-induced venodilation were superimposable in WT and Thr164Ile beta2-AR subjects.


CONCLUSIONS
beta2-AR-mediated dilation of human hand veins is influenced by the 3 most common beta2-AR haplotypes and blunted in subjects heterozygous for Thr164Ile beta2-AR. Long-term terbutaline treatment desensitizes venous beta2-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).
Bruck
Heike
H
Department of Nephrology and Pathophysiology, University of Essen Medical School, Essen, Germany.
Leineweber
Kirsten
K
Park
Jinny
J
Weber
Melanie
M
Heusch
Gerd
G
Philipp
Thomas
T
Brodde
Otto-Erich
OE
D058666:Adrenergic beta-2 Receptor Agonists; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000328:Adult; D004305:Dose-Response Relationship, Drug; D005260:Female; D006225:Hand / Q000098:blood supply; D006239:Haplotypes; D006339:Heart Rate / Q000187:drug effects; D006579:Heterozygote; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D010656:Phenylephrine / Q000494:pharmacology; D011110:Polymorphism, Genetic / Q000235:genetics; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics*; D012039:Regional Blood Flow / Q000187:drug effects; D013726:Terbutaline / Q000494:pharmacology; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects / Q000235:genetics*; D014680:Veins / Q000187:drug effects / Q000502:physiology
D058666:Adrenergic beta-2 Receptor Agonists; D000318:Adrenergic beta-Agonists; D018343:Receptors, Adrenergic, beta-2; D014662:Vasoconstrictor Agents; D010656:Phenylephrine; D013726:Terbutaline