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Effect of the A rg389 G ly β 1 ‐adrenoceptor polymorphism on plasma renin activity and heart rate, and the genotype‐dependent response to metoprolol treatment
Author(s) -
Petersen Morten,
Andersen Jon T,
JimenezSolem Espen,
Broedbaek Kasper,
Hjelvang Brian R,
Henriksen Trine,
Frandsen Erik,
Forman Julie L,
TorpPedersen Christian,
Køber Lars,
Poulsen Henrik E
Publication year - 2012
Publication title -
clinical and experimental pharmacology and physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.752
H-Index - 103
eISSN - 1440-1681
pISSN - 0305-1870
DOI - 10.1111/j.1440-1681.2012.05736.x
Subject(s) - metoprolol , plasma renin activity , medicine , endocrinology , heart rate , placebo , genotype , renin–angiotensin system , blood pressure , chemistry , gene , biochemistry , alternative medicine , pathology
Summary A gene–drug interaction has been indicated between β 1 ‐adrenoceptor‐selective beta‐blockers and the A rg389 G ly polymorphism (rs1801253) in the adrenergic beta‐1 receptor gene ( ADRB 1 ). In the present study, we investigated the effect of the ADRB 1 A rg389 G ly polymorphism on plasma renin activity ( PRA ) and heart rate ( HR ), as well as genotype‐dependent responses to metoprolol and exercise. Twenty‐nine healthy male subjects participated in two treatment periods (placebo and 200 mg/day 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 G ly/ G ly subjects than in A rg/ A rg subjects after both placebo ( P = 0.030) and metoprolol ( P = 0.020) treatment. After placebo, the exercise‐induced increase in PRA was greater in G ly/ G ly than A rg/ G ly and A rg/ A rg subjects ( P = 0.033). The linear association between log( PRA ) and log(metoprolol concentration) varied significantly between genotypes ( P = 0.024). In G ly/ G ly subjects, PRA decreased significantly with metoprolol concentration before ( P = 0.025) and after exercise ( P < 0.001), whereas in A rg/ G ly and A rg/ A rg subjects metoprolol concentration had no effect on PRA . The effect of metoprolol concentration on PRA in G ly/ G ly subjects was enhanced by exercise ( P = 0.044). No significant differences in HR were seen between genotype groups. Resting PRA was lower in G ly/ G ly than A rg/ A rg subjects and the effect of exercise and metoprolol concentration on PRA was stronger in G ly/ G ly subjects than with the other two genotypes. Thus, G ly/ G ly heart failure patients may require lower doses of metoprolol than other patients to block neurohumoral hyperactivity.