PROTECTIVE EFFECTS OF IVABRADINE (ALONE AND COMBINED WITH ATENOLOL OR ENALAPRIL) ON EXPERIMENTALLY-INDUCED ACUTE MYOCARDIAL INFARCTION IN ALBINO RATS

Abstract

Background: Cardiovascular disease (CVD) is the leading cause of death worldwide. Deaths are mostly attributable to coronary artery disease (CAD). Ivabradine, a pure heart rate lowering agent, acts by inhibiting the pacemaker If current in the sinoatrial node. It can be used for treatment of heart failure and stable angina with the main drugs for CVD.
Objectives: To determine the cardioprotective effects of ivabradine pretreatment alone and in combination with each of atenolol and enalapril on acute myocardial infarction (MI) in rats.
Materials & Methods: Eighty four rats were divided into seven groups (12 rats each): Group 1: sham-operated group; Group 2: control (untreated) MI group; Group 3: ivabradine-pretreated group; Group 4: atenolol-pretreated group; Group 5: enalapril-pretreated group; Group 6: ivabradine and atenolol-pretreated group; and Group 7: ivabradine and enalapril-pretreated group. Rats received drugs orally by gavage daily for 6 days. On the sixth day, acute MI was induced by persistent complete left coronary artery ligation. The parameters studied were mean arterial blood pressure, ECG changes (heart rate, ST height and T-wave voltage), serum levels of creatine kinase MB isoenzyme (CK-MB), cardiac troponin-I (cTnI), high-sensitivity C-reactive protein (hs-CRP) and N-terminal pro-brain-type natriuretic peptide (NT-proBNP), tissue levels of superoxide dismutase (SOD), reduced glutathione (GSH), Bcl-2-associated X protein (Bax) and the % of infarct size of the left ventricle.
Results: Coronary artery ligation resulted in significant elevation in ST height, T-wave voltage, serum levels of CK-MB, cTnI, hs-CRP and NT-proBNP and tissue levels of Bax, with significant reduction of the tissue levels of SOD & GSH and produced 54% infarct size of the left ventricle. Oral pretreatment with ivabradine has cardioprotective effect against acute MI as evidenced by significantly lower ST height, T-wave voltage, serum levels of CK-MB, cTnI, hs-CRP and NT-proBNP and tissue levels of Bax, with significantly higher tissue levels of SOD & GSH and significantly lower infarct size (into 39%). Oral pretreatment with combination of ivabradine and atenolol produced greater cardioprotection against acute MI than observed with ivabradine alone evidenced by significantly lower ST height, T-wave voltage, serum levels of CK-MB, cTnI, hs-CRP and NT-proBNP and tissue level of Bax, with significantly higher tissue levels of SOD & GSH and significantly lower infarct size (into 23%). Although, the effects of oral pretreatment with combination of ivabradine and enalapril on ST height, T-wave voltage, tissue levels of SOD & GSH and % of infarct size were not significantly different from that of ivabradine; however, this combination caused significant reduction of serum levels of CK-MB, cTnI, hs-CRP and NT-proBNP and tissue level of Bax as compared to the effect of ivabradine alone.
Conclusion: Ivabradine possesses protective effects against acute MI and these effects are lower than the protective effects of atenolol; but higher than that of enalapril. Concomitant administration of ivabradine with either atenolol or enalapril provides greater cardioprotection against acute MI than ivabradine alone and these effects are greatest when ivabradine is combined with atenolol.
Keywords: cardiovascular disease, acute coronary syndrome, myocardial infarction, If current, ivabradine, atenolol, enalapril