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Gly389Arg polymorphism of β 1 ‐adrenergic receptor is associated with the cardiovascular response to metoprolol
Author(s) -
Liu Jie,
Liu ZhaoQian,
Tan ZhiRong,
Chen XiaoPing,
Wang LianSheng,
Zhou Gan,
Zhou HongHao
Publication year - 2003
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/s0009-9236(03)00224-8
Subject(s) - metoprolol , heart rate , medicine , endocrinology , dose , blood pressure , in vivo , biology , microbiology and biotechnology
Objectives Our objectives were to determine whether the Gly389 polymorphism of the β 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 β 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 β‐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 β 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 β 1 ‐adrenergic receptor Gly389Arg polymorphism is of major functional importance in vivo. Clinical Pharmacology & Therapeutics (2003) 74 , 372–379; doi: 10.1016/S0009‐9236(03)00224‐8