Liu Jie, Liu Zhao-Qian, Tan Zhi-Rong, Chen Xiao-Ping, Wang Lian-Sheng, Zhou Gan, Zhou Hong-Hao
Pharmacogenetics Research Institute, Institute of Clinical Pharmacology, Central South University, Changsha, Hunan, China.
Clin Pharmacol Ther. 2003 Oct;74(4):372-9. doi: 10.1016/S0009-9236(03)00224-8.
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.
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.
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).
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.
我们的目的是确定β1 - 肾上腺素能受体的Gly389多态性在体内是否表现出反应性降低，并检验Gly389Arg多态性影响美托洛尔对血压和心率反应的假说。
通过聚合酶链反应 - 限制性片段长度多态性分析确定β1 - 肾上腺素能受体基因型。比较8名Gly389纯合子健康中国男性和8名Arg389纯合子健康中国男性运动诱导的心率增加情况，以确定其在体内的功能意义。所有受试者每8小时给予25、50或75毫克美托洛尔；给药剂量随机安排，每个剂量给药1天。通过静息和运动时心率及血压的降低来衡量β受体阻滞程度。使用高效液相色谱 - 荧光检测法测定血浆美托洛尔浓度。
运动导致心率随工作量增加。Arg389和Gly389纯合子之间运动诱导的心率增加无差异。口服美托洛尔使两组静息和运动时心率均出现显著的剂量依赖性降低。美托洛尔3个剂量水平下，Arg389纯合子受试者静息心率降低分别为6.3%±0.8%、10.1%±1.0%、14.4%±1.4%，Gly389纯合子受试者分别为4.1%±0.7%、6.2%±1.1%、10.9%±1.3%（P = 0.008）。我们还发现运动心率方面存在差异（Arg389受试者为8.9%±0.5%、14.0%±0.9%、20.1%±1.5%，Gly389受试者为6.6%±0.7%、11.7%±1.0%、16.4%±1.3%；P = 0.017）以及收缩压方面存在差异（Arg389受试者为5.9%±0.7%、9.2%±1.0%、11.6%±1.2%，Gly389受试者为4.6%±0.5%、6.0%±0.8%、9.9%±0.9%；P = 0.011）。然而，舒张压下降的差异无统计学意义（P = 0.442）。
在年轻男性中国受试者中，β1 - 肾上腺素能受体的Arg389变异体对美托洛尔的反应比Gly389变异体更大。这些数据表明β1 - 肾上腺素能受体Gly389Arg多态性在体内具有重要的功能意义。
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