Effect of the Arg389Gly β₁-adrenoceptor polymorphism on plasma renin activity and heart rate, and the genotype-dependent response to metoprolol treatment

Clin Exp Pharmacol Physiol. 2012 Sep;39(9):779-85. doi: 10.1111/j.1440-1681.2012.05736.x.


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.

Trial registration: ClinicalTrials.gov NCT00885651.

Publication types

  • Clinical Trial
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic beta-1 Receptor Antagonists / administration & dosage
  • Adrenergic beta-1 Receptor Antagonists / blood
  • Adrenergic beta-1 Receptor Antagonists / pharmacokinetics
  • Adrenergic beta-1 Receptor Antagonists / pharmacology*
  • Adult
  • Alleles
  • Amino Acid Substitution
  • Cross-Over Studies
  • Denmark
  • Dose-Response Relationship, Drug
  • Drug Resistance
  • Exercise Test
  • Genetic Association Studies
  • Heart Rate / drug effects*
  • Humans
  • Male
  • Metoprolol / administration & dosage
  • Metoprolol / blood
  • Metoprolol / pharmacokinetics
  • Metoprolol / pharmacology*
  • Motor Activity*
  • Polymorphism, Single Nucleotide*
  • Receptors, Adrenergic, beta-1 / genetics*
  • Receptors, Adrenergic, beta-1 / metabolism
  • Renin / blood*
  • Renin-Angiotensin System / drug effects
  • Young Adult


  • ADRB1 protein, human
  • Adrenergic beta-1 Receptor Antagonists
  • Receptors, Adrenergic, beta-1
  • Renin
  • Metoprolol

Associated data

  • ClinicalTrials.gov/NCT00885651