Gly389Arg polymorphism of beta1-adrenergic receptor is associated with the cardiovascular response to metoprolol.
OBJECTIVE
Our objectives were to determine whether the Gly389 polymorphism of the beta(1)-adrenergic receptor exhibits reduced responsiveness in vivo and to test the hypothesis that the Gly389Arg polymorphism affects the blood pressure and heart rate response to metoprolol.


METHODS
beta(1)-Adrenergic receptor genotype was determined by polymerase chain reaction-restriction fragment length polymorphism assay. Exercise-induced heart rate increases were compared to determine the functional significance in vivo in 8 healthy Chinese men homozygous for Gly389 and 8 homozygous for Arg389. All of the subjects were given 25, 50, or 75 mg of metoprolol every 8 hours; the dosages were given in a random order, and each dosage was given for 1 day. The degree of beta-blockade was measured as the reduction in resting and exercise heart rates and blood pressures. Plasma metoprolol concentrations were measured by the use of HPLC-fluorescence detection.


RESULTS
Exercise led to a workload-dependent increase in heart rate. There were no differences in exercise-induced heart rate increases between Arg389 and Gly389 homozygotes. Oral metoprolol caused significant dose-dependent decreases in both resting and exercise heart rates in both groups. The reductions in the resting heart rate in 3 dosage levels of metoprolol were 6.3% +/- 0.8% versus 4.1% +/- 0.7%, 10.1% +/- 1.0% versus 6.2% +/- 1.1%, and 14.4% +/- 1.4% versus 10.9% +/- 1.3% in homozygous Arg389 subjects and Gly389 subjects, respectively (P =.008). We also found differences with respect to the exercise heart rate (8.9% +/- 0.5%, 14.0% +/- 0.9%, and 20.1% +/- 1.5% in Arg389 subjects and 6.6% +/- 0.7%, 11.7% +/- 1.0%, and 16.4% +/- 1.3% in Gly389 subjects; P =.017) and systolic pressure (5.9% +/- 0.7%, 9.2% +/- 1.0%, and 11.6% +/- 1.2% in Arg389 subjects and 4.6% +/- 0.5%, 6.0% +/- 0.8%, and 9.9% +/- 0.9% in Gly389 subjects; P =.011). However, the difference in the fall in diastolic pressure was not statistically significant (P =.442).


CONCLUSIONS
The Arg389 variant of the beta(1)-adrenergic receptor was associated with a greater response to metoprolol than that of Gly389 in young, male Chinese subjects. These data suggested that the beta(1)-adrenergic receptor Gly389Arg polymorphism is of major functional importance in vivo.
Liu
Jie
J
Pharmacogenetics Research Institute, Institute of Clinical Pharmacology, Central South University, Changsha, Hunan, China.
Liu
Zhao-Qian
ZQ
Tan
Zhi-Rong
ZR
Chen
Xiao-Ping
XP
Wang
Lian-Sheng
LS
Zhou
Gan
G
Zhou
Hong-Hao
HH
D000328:Adult; D000959:Antihypertensive Agents / Q000097:blood / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects*; D015444:Exercise; D023281:Genomics; D005838:Genotype; D006339:Heart Rate / Q000187:drug effects*; D006801:Humans; D008297:Male; D008790:Metoprolol / Q000097:blood / Q000494:pharmacology*; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D018342:Receptors, Adrenergic, beta-1 / Q000235:genetics*
D000959:Antihypertensive Agents; D018342:Receptors, Adrenergic, beta-1; D008790:Metoprolol