Effect of the Arg389Gly β₁-adrenoceptor polymorphism on plasma renin activity and heart rate, and the genotype-dependent response to metoprolol treatment.
1. A gene-drug interaction has been indicated between β₁-adrenoceptor-selective beta-blockers and the Arg389Gly polymorphism (rs1801253) in the adrenergic beta-1 receptor gene (ADRB1). In the present study, we investigated the effect of the ADRB1 Arg389Gly polymorphism on plasma renin activity (PRA) and heart rate (HR), as well as genotype-dependent responses to metoprolol and exercise. 2. 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. 3. Before exercise, median PRA was lower in Gly/Gly subjects than in Arg/Arg subjects after both placebo (P = 0.030) and metoprolol (P = 0.020) treatment. After placebo, the exercise-induced increase in PRA was greater in Gly/Gly than 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), whereas in Arg/Gly and Arg/Arg subjects 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. 4. Resting PRA was lower in Gly/Gly than 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. Thus, Gly/Gly heart failure patients may require lower doses of metoprolol than other patients to block neurohumoral hyperactivity.
Laboratory of Clinical Pharmacology, Rigshospitalet-Copenhagen University Hospital, Copenhagen, Denmark. mortenpetersen@rh.dk
Morten
M
Petersen
Jon T
JT
Andersen
Espen
E
Jimenez-Solem
Kasper
K
Broedbaek
Brian R
BR
Hjelvang
Trine
T
Henriksen
Erik
E
Frandsen
Julie L
JL
Forman
Christian
C
Torp-Pedersen
Lars
L
Køber
Henrik E
HE
Poulsen
D058671:Adrenergic beta-1 Receptor Antagonists / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D000328:Adult; D000483:Alleles; D019943:Amino Acid Substitution; D018592:Cross-Over Studies; D003718:Denmark; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D005080:Exercise Test; D056726:Genetic Association Studies; D006339:Heart Rate / Q000187:drug effects*; D006801:Humans; D008297:Male; D008790:Metoprolol / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D009043:Motor Activity; D020641:Polymorphism, Single Nucleotide; D018342:Receptors, Adrenergic, beta-1 / Q000235:genetics* / Q000378:metabolism; D012083:Renin / Q000097:blood*; D012084:Renin-Angiotensin System / Q000187:drug effects; D055815:Young Adult
C547787:ADRB1 protein, human; D058671:Adrenergic beta-1 Receptor Antagonists; D018342:Receptors, Adrenergic, beta-1; D012083:Renin; D008790:Metoprolol