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期刊论文
Gly389Arg polymorphism of 1-adrenergicreceptor is associated with the cardiovascular response to metoprolol
CLINICAL PHARMACOLOGY & THERAPEUTICS OCTOBER 2003,-0001,():
Objectives: Our objectives were to determine whether the Gly389 polymorphism of the β1-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: β1-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 75mg of metoprolol every 8 hours; the dosages were given in a random order, and each dosage was given for β1 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 exerciseinduced 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).
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