Naunyn-Schmiedeberg's Archives of Pharmacology

, Volume 372, Issue 2, pp 115–124 | Cite as

Interaction between simvastatin and metoprolol with respect to cardiac β-adrenoceptor density, catecholamine levels and perioperative catecholamine requirements in cardiac surgery patients

  • A. Franka Nette
  • Getu Abraham
  • Fritz Rupert Ungemach
  • Reinhard Oertel
  • Wilhelm Kirch
  • Kirsten Leineweber
  • Friedrich-Wilhelm Mohr
  • Stefan Dhein
Original Article
First Online:
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Accepted:

Abstract

β-Blockade is a standard cardiovascular therapy known to induce the up-regulation of β-adrenoceptor density. Upon ligand-binding, β-adrenoceptors are normally internalised via the arrestin pathway, and after dissociation they are re-inserted into the membrane. This means that at high catecholamine levels the adrenoceptor density is low and under β-blockade it is high. The insertion of receptors into the membrane is often dependent on farnesylation processes that can be inhibited by statins. We carried out a prospective, controlled, observational study to determine whether β-blockade-induced up-regulation of β-adrenoceptor density is attenuated by statin therapy and whether this would subsequently affect catecholamine consumption during surgery. We obtained pre-operative blood samples and intra-operative biopsies of the right atrial appendage from 39 patients (age: 65±5 years; BMI: 28±1) undergoing coronary bypass surgery with or without simvastatin (20 mg/day) therapy and with or without concomitant metoprolol therapy (50 mg/day).. The atrial tissue was used for radioligand-binding studies with (−)-[125I]-iodocyanopindolol (ICYP) and for assessment of the β-adrenoceptor subtype distribution following standard protocols. In the blood samples, plasma adrenaline and noradrenaline concentrations were determined using HPLC. In all tissue samples, we found a total β-adrenoceptor density of 38±4 fmol/mg protein in untreated controls; this which was up-regulated to 55±5 fmol/mg protein in patients receiving metoprolol. This increase in receptor number was nearly prevented completely by simvastatin therapy (42±5 fmol/mg protein). The up-regulation could be attributed to increases in the β1-adrenoceptor subtype. In contrast, simvastatin alone had no effect on β-adrenoceptor density. Pre-operative adrenaline levels were slightly reduced in all drug therapy groups (nonsignificant differences), while the levels noradrenaline were not significantly different among the groups. With respect to the perioperative catecholamine requirements, patients on metoprolol needed significantly less dopamine than control patients, while patients undergoing simvastatin/metoprolol therapy needed as much as the controls. The post-operative total catecholamine requirements were not different among the four groups of patients. There were no differences in plasma metoprolol concentration between patients receiving metoprolol alone and those receiving a combination of metoprolol and simvastatin. In conclusion: Simvastatin therapy seems to counter-regulate the up-regulation of β-adrenoceptor density. In the up-regulated state induced by metoprolol therapy, the patients seemed to need less catecholamines during cardiac surgery, which may be due to the higher number of β-adrenoceptors. Additional simvastatin therapy did not reduce post-operative catecholamine consumption.

Keywords

Simvastatin Metoprolol Statin Therapy Plasma Catecholamine Renal Sympathetic Nerve Activity 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.
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Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • A. Franka Nette
    • 1
  • Getu Abraham
    • 2
  • Fritz Rupert Ungemach
    • 2
  • Reinhard Oertel
    • 3
  • Wilhelm Kirch
    • 3
  • Kirsten Leineweber
    • 4
  • Friedrich-Wilhelm Mohr
    • 1
  • Stefan Dhein
    • 1
  1. 1.Clinic for Cardiac Surgery, Heart Centre LeipzigUniversity of LeipzigLeipzigGermany
  2. 2.Institute for Veterinary Pharmacology and ToxicologyUniversity of LeipzigLeipzigGermany
  3. 3.Institute of Clinical Pharmacology, Carl Gustav Carus KlinikumUniversity of DresdenDresdenGermany
  4. 4.Institute for PathophysiologyUniversity of EssenEssenGermany

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