3-hydroxy-3-methyl-glytaryl coenzyme A (HMG-CoA) reductase inhibitors have been proved to be extremely useful in the management of hypercholesterolemia, as well as in prevention of primary and secondary coronary heart disease. However, they may produce rare but severe muscle-related symptoms such as myopathy and rhabdomyolysis. Recent findings in vitro have shown that statins could reduce cardiomyocyte viability. The correlation between statin cardiotoxicity, assessed in vitro, and cardiac efficiency, investigated in vivo has not been estimated so far. Diltiazem as CYP3A4 inhibitor, is well recognized risk factor of skeletal muscles myopathy, if co-administered with simvastatin. It is not known whether such interaction affects myocardial efficiency. A combination of pathological and biochemical studies were performed in myopathy model induced by simvastatin as well. causing haemodynamic changes. The aim of the experiment was to establish the impact of simvastatin, at the dose provoking myopathy of skeletal muscles, and co-administered with diltiazem, on myocardium efficiency, defining as cardiac output (COI), after continuous infusion of dopamine as well as the influence on the histopathological and biochemical changes. The experiments were performed on New Zealand white rabbits. The animals were divided into four groups receiving: 0.2% MC (control group); diltiazem (5 mg/kg); simvastatin (50 mg/kg); simvastatin + diltiazem, for 14 days (po). Dopamine did not cause a statistically significant increase in COI in rabbits receiving simvastatin alone. Diltiazem significantly increased the cardiac output index, maximally by 23%, if given simultaneously with simvastatin. The combined administration of simvastatin with diltiazem caused a marked increase in cardiac output index, as compared to simvastatin alone, too. Simultaneous administration of simvastatin and diltiazem caused 23-fold increase (P< 0.01), in rabbit serum CK levels and 20-fold increase (P=0.056) in TnI levels, as compared to the initial values. Also in these rabbits significant increase in CK (12411,60 vs 839,87 IU/L) and TnI (0,26 vs 0,014 ng/mL) as compared to control group were observed. Significant increase in CK (12411,60 vs 1100,92 IU/L) and TnI (0,26 vs 0,012 ng/mL) as compared to diltiazem alone were noted, too. Several lesions such as necrosis with macrophagic infiltration and single muscle degradation in myocardium were found. However, those changes seem to had no influence on cardiac efficiency which was even improved. It may suggest another mechanism, of drug-drug interaction than the one based on CYP3A4 inhibition considering the statin impact on skeletal and cardiac muscle.

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1. SIMVASTATIN INTENSIFY HEART RATE DEPRESSION AFTER METOPROLOL AND ATROPINE ADMINISTRATION IN NORMOCHOLESTEROLAEMIC RATS