The Effect of the Arg389Gly Beta-1 Adrenoceptor Polymorphism on Plasma Renin Activity and Heart Rate and the Genotype-Dependent Response to Metoprolol Treatment

A gene-drug interaction has been indicated between beta-1 selective beta-blockers and the Arg389Gly polymorphism (rs1801253) in the adrenergic beta-1 receptor gene (ADRB1). We studied the effect of the ADRB1 Arg389Gly polymorphism on plasma renin activity (PRA) and heart rate (HR) and the genotype-dependent response to metoprolol and exercise. Twenty-nine healthy male subjects participated in 2 treatment periods (placebo and metoprolol). A 15-min submaximal exercise test was performed after each treatment period, and PRA and HR were measured before and after exercise. Before exercise, median PRA was lower in Gly/Gly subjects than in Arg/Arg subjects after both placebo (P = 0.030) and metoprolol treatment (P = 0.020). After placebo, the exercise-induced PRA increase was greater in Gly/Gly than in Arg/Gly and Arg/Arg subjects (P = 0.033). The linear association between log(PRA) and log(metoprolol concentration) varied significantly between genotypes (P = 0.024). In Gly/Gly subjects, PRA decreased significantly with metoprolol concentration before (P = 0.025) and after exercise (P <0.001), while in Arg/Gly and Arg/Arg metoprolol concentration had no effect on PRA. The effect of metoprolol concentration on PRA in Gly/Gly subjects was enhanced by exercise (P = 0.044). No significant differences in HR were seen between genotype groups. Resting PRA was lower in Gly/Gly than in Arg/Arg subjects, and the effect of exercise and metoprolol concentration on PRA was stronger in Gly/Gly subjects than with the other two genotypes. Gly/Gly heart failure patients might require lower doses of metoprolol than other patients to block neurohumoral hyperactivity. © 2012 The Authors Clinical and Experimental Pharmacology and Physiology © 2012 Blackwell Publishing Asia Pty Ltd.