title: Concomitant administration of simvastatin with ivabradine in contrast to metoprolol intensifies slowing of heart rate in normo- and hypercholesterolemic rats.
abstract: BACKGROUND
  β-Blockers play a significant role in therapeutic heart rate (HR) management and angina control. In patients who are unable to tolerate β-blockers ivabradine could be particularly useful. The aim of the study was to establish whether concomitant administration of simvastatin with ivabradine or metoprolol had any effect on rat HR and blood pressure (BP).
  
  
  METHODS
  The experiments were performed in hyper- and normocholesterolemic outbred Wistar rats. Animals were divided into 2 groups: receiving during 4 weeks normal diet (normocholesterolemic rats) or diet with 5% cholesterol and 2.5% cholic acid (hypercholesterolemic rats). Then rats received placebo (0.1% methylcellulose), 2) metoprolol 30 mg/kg bw; 3) ivabradine 10 mg/kg bw; 4) simvastatin 10 mg/kg bw; 5) simvastatin 10 mg/kg bw + metoprolol 30 mg/kg bw; 6) simvastatin 10 mg/kg bw + ivabradine 10 mg/kg bw. Drugs were given during a 4-week period. HR and BP measure were provided by an Isotec pressure transducer connected to a direct current bridge amplifier. For the further lipid profile examination, 0.25 ml of blood samples were taken.
  
  
  RESULTS
  After administration of ivabradine with simvastatin to normocholesterolemic and hypercholesterolemic rats the mean HR was significantly reduced as compared to rats receiving simvastatin (312.0 ±30.2 min(-1) vs. 430.7 ±27.8 min(-1), p<0.05); (329.8 ±24.2 min(-1) vs. 420.5 ±9.2 min(-1), p<0.05) or ivabradine alone (312.0 ±30.2 min(-1) vs. 350.2 ±16.0 min(-1), p<0.05); (329.8 ±24.2 min(-1) vs. 363.0 ±21.7 min(-1), p<0.05).
  
  
  CONCLUSIONS
  Concomitant administration of simvastatin with ivabradine intensified slowing of HR, although it did not influence BP in normo-and hypercholesterolemic rats. Statin-induced intensification of HR deceleration after metoprolol administration was not observed.
authors.affiliation: Department of Biopharmacy, Medical University of Lodz, Poland.
authors.forename: Jacek
authors.initials: J
authors.lastname: Owczarek
authors.forename: Magdalena
authors.initials: M
authors.lastname: Jasińska
authors.forename: Jarosław
authors.initials: J
authors.lastname: Drożdż
authors.forename: Daria
authors.initials: D
authors.lastname: Orszulak-Michalak