Human
2
-adrenergic receptor gene
haplotypes and venodilation in vivo
Background and Objective:
2
-Adrenergic receptors (
2
-ARs) are polymorphic. In vitro studies have shown
that agonist-promoted down-regulation is enhanced for Arg16Gly and blunted for Gln27Glu
2
-AR vari-
ants; Thr164Ile
2
-ARs exhibit reduced responsiveness to agonist stimulation. Our objective was to deter-
mine whether
2
-AR polymorphisms affect
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
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
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
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
2
-AR;
after terbutaline treatment, dose-response curves for terbutaline-induced venodilation were superimposable
in WT and Thr164Ile
2
-AR subjects.
Conclusion:
2
-AR–mediated dilation of human hand veins is influenced by the 3 most common
2
-AR
haplotypes and blunted in subjects heterozygous for Thr164Ile
2
-AR. Long-term terbutaline treatment
desensitizes venous
2
-AR in a haplotype-dependent manner, with haplotype A (Arg16Gln27Thr164) show-
ing greater desensitization than haplotype B (Gly16Gln27Thr164), which shows greater desensitization than
haplotype C (Gly16Glu27Thr164). (Clin Pharmacol Ther 2005;78:232-8.)
Heike Bruck, MD, Kirsten Leineweber, PhD, Jinny Park, BSc, Melanie Weber,
Gerd Heusch, MD, Thomas Philipp, MD, and Otto-Erich Brodde, PhD Essen, Germany
2
-Adrenergic receptors (
2
-ARs) play an important
role in the regulation of vascular and bronchial smooth
muscle tone,
1
glands, lymphocytes, and hepatocytes.
They also exist in the human heart and contribute to the
regulation of heart rate and contractility.
2
2
-ARs are
polymorphic; at least 3 functionally important single-
nucleotide polymorphisms have been described—
Arg16Gly, Gln27Glu, and Thr164Ile.
3-5
In vitro, func-
tional properties of Gly16 and Glu27
2
-AR variants do
not differ from those of wild-type (WT)
2
-AR
(Arg16Gln27Thr164).
6
In contrast, the Ile164
2
-AR
variant exhibited extensive signaling defects.
7
Thus
isoproterenol hydrochloride (INN, isoprenaline), epi-
nephrine, and norepinephrine had a 4-fold lower affin-
ity for Ile164
2
-AR transfected in Chinese hamster
fibroblasts (CHW) cells than for WT
2
-AR. Moreover,
the Ile164 variant exhibits reduced basal and agonist-
induced activation of adenylyl cyclase and a rightward
shift of the agonist concentration-effect curve, suggest-
ing a diminished
2
-AR–G protein interaction.
7
In
vivo, in humans heterozygous for Thr164Ile
2
-AR
(homozygous Ile164 variants are not found in the hu-
man population
3-5
), cardiac and venous
2
-AR re-
sponses were blunted compared with responses in sub-
jects carrying homozygous Thr164.
8-10
From the Departments of Nephrology and Pathophysiology, Univer-
sity of Essen Medical School.
Supported by grants from the Nationales Genomforschungsnetz-
Förderzeichen (01GS0170) and from the Deutsche Forschungsge-
meinschaft (DFG BR 526/8-1 to Dr Brodde).
Received for publication March 2, 2005; accepted June 2, 2005.
Reprint requests: Otto-Erich Brodde, PhD, University of Essen Med-
ical School, Departments of Nephrology and Pathophysiology,
Hufelandstrasse 55, D-45147 Essen, Germany.
E-mail: otto-erich.brodde@uni-essen.de
0009-9236/$30.00
Copyright © 2005 by the American Society for Clinical Pharmacology
and Therapeutics.
doi:10.1016/j.clpt.2005.06.002
232