title: Interaction between simvastatin and metoprolol with respect to cardiac beta-adrenoceptor density, catecholamine levels and perioperative catecholamine requirements in cardiac surgery patients.
abstract: Beta-blockade is a standard cardiovascular therapy known to induce the up-regulation of beta-adrenoceptor density. Upon ligand-binding, beta-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 beta-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 beta-blockade-induced up-regulation of beta-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 beta-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 beta-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 beta1-adrenoceptor subtype. In contrast, simvastatin alone had no effect on beta-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.
  
  
  CONCLUSIONS
  Simvastatin therapy seems to counter-regulate the up-regulation of beta-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 beta-adrenoceptors. Additional simvastatin therapy did not reduce post-operative catecholamine consumption.
authors.affiliation: Clinic for Cardiac Surgery, Heart Centre Leipzig, University of Leipzig, Leipzig, Germany.
authors.forename: A Franka
authors.initials: AF
authors.lastname: Nette
authors.forename: Getu
authors.initials: G
authors.lastname: Abraham
authors.forename: Fritz Rupert
authors.initials: FR
authors.lastname: Ungemach
authors.forename: Reinhard
authors.initials: R
authors.lastname: Oertel
authors.forename: Wilhelm
authors.initials: W
authors.lastname: Kirch
authors.forename: Kirsten
authors.initials: K
authors.lastname: Leineweber
authors.forename: Friedrich-Wilhelm
authors.initials: FW
authors.lastname: Mohr
authors.forename: Stefan
authors.initials: S
authors.lastname: Dhein
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000008:administration & dosage / Q000627:therapeutic use*; D000368:Aged; D020517:Atrial Appendage / Q000187:drug effects / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D006348:Cardiac Surgical Procedures; D002395:Catecholamines / Q000008:administration & dosage* / Q000097:blood* / Q000627:therapeutic use; D001026:Coronary Artery Bypass; D003327:Coronary Disease / Q000097:blood / Q000378:metabolism / Q000601:surgery; D004338:Drug Combinations; D004347:Drug Interactions; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D008297:Male; D008790:Metoprolol / Q000008:administration & dosage / Q000097:blood / Q000627:therapeutic use*; D008875:Middle Aged; D019990:Perioperative Care; D011446:Prospective Studies; D011943:Receptors, Adrenergic, beta / Q000032:analysis / Q000187:drug effects* / Q000378:metabolism; D019821:Simvastatin / Q000008:administration & dosage / Q000627:therapeutic use*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000319:Adrenergic beta-Antagonists; D002395:Catecholamines; D004338:Drug Combinations; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011943:Receptors, Adrenergic, beta; D019821:Simvastatin; D008790:Metoprolol