Abstract
Ivabradine is a novel heart rate lowering agent that inhibits If ionic current in the sinus node and demonstrates antiischaemic and antianginal activity. The aim of the paper was to investigate the effect its dose-dependent drug-drug interaction with simvastatin inhibitor HMGCo-A has on PAI-1 blood level, heart rate and blood pressure. The experiments were performed in hyper- and normocholesterolemic Wistar rats receiving simvastatin (1 and 20 mg × kg−1 bw) with ivabradine (10 mg × kg−1 bw) during a 4-week period. Ivabradine exacerbated the decrease of PAI-1 in normocholesterolemic animals receiving simvastatin at a dose of 1 mg/kg bw and was not observed to have any significant influence on the PAI-1 values in rats receiving 20 mg × kg−1 bw simvastatin. Ivabradine, coadministered with simvastatin given at a dose of 20 mg × kg−1 bw, significantly slowed the heart rate in normocholesterolaemic and hypercholesterolaemic groups as compared to the group receiving ivabradine alone. Conclusion. The administration of ivabradine to normocholesterolaemic and hypercholesterolaemic rats receiving simvastatin significantly exacerbated the slowing of heart rate with no effect on blood pressure. The administration of ivabradine has been shown to demonstrate different effects on PAI-1 values depending on lipid disorders.
Highlights
The resting heart rate value acts as an independent factor of the risk associated with cardiovascular problems [1,2,3]
In normocholesterolaemic and hypercholesterolaemic rats receiving simvastatin at doses of 1 and 20 mg × kg−1 bw alone, no significant differences were seen in the heart rate disturbances compared to control groups
The heart rate values after concomitant administration of ivabradine and simvastatin at a dose of 1 mg × kg−1 bw to normocholesterolaemic rats were significantly decreased compared to the control group (342.3 ± 28.6 versus 434.8 ± 17.2 min−1) and compared to the group receiving simvastatin alone
Summary
The resting heart rate value acts as an independent factor of the risk associated with cardiovascular problems [1,2,3]. In ischaemic heart disease (IHD) patients, the role played by HMGCo-A inhibitors in the prevention of cardiovascular events is well established. Their beneficial activity is dependent on the limitation of cholesterol synthesis as well as cholesterol-independent “pleiotropic” effects [12]. It has been shown in earlier clinical studies that simvastatin at a dose of 40 mg/day given for a period of 8 weeks significantly reduced the levels of inflammatory markers [13] as well as inhibited the activity of the circulating fibrinolysis inhibitor factor-plasminogen activator inhibitor 1(PAI-1) [14]. The influence on fibrinolysis processes were observed depending on the “mechanism that involves geranylgeranyl-modified intermediates.”
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