Cardioprotective effect of trimetazidine and nifedipine in guinea-pig hearts subjected to ischaemia

Abstract

The cardioprotective effects of nifedipine and trimetazidine were evaluated in the Langendorff heart, the working heart and the heart-lung preparation of the guinea-pig. The effects of pretreatment with the drugs on cardiac function and on high energy phosphate content after global ischaemia were determined. Nifedipine was 1000-fold more active than trimetazidine in depressing cardiac functional parameters. In the Langendorff heart, nifedipine, but not trimetazidine, increased the coronary flow. With the exception of trimetazidine (4 x 10-5 mol/l) in the Langendorff heart, nifedipine and trimetazidine markedly improved and in a similar fashion, the recovery of cardiac mechanical parameters in the three models of myocardial ischaemia. Pretreatment with nifedipine, but not with trimetazidine, resulted in slightly but statistically not significant higher ATP-levels after global ischaemia in the working heart and in the heart-lung preparation. After reperfusion, the cardioprotective effect of nifedipine was associated with increased ATP-levels, whereas that of trimetazidine was merely related to increased phosphocreatine (PCr) levels. In the pithed rat, trimetazidine did not influence the vasoconstrictor response to the selective α1-adrenoceptor agonist cirazoline or to the selective α2-adrenoceptor agonist B-HT 920. The latter response is known to be strongly dependent on the influx of extracellular calcium. Nifedipine caused a pronounced inhibition of vasoconstriction evoked by B-HT 920. These results indicate that trimetazidine is devoid of calcium entry blocking activity. The data obtained clearly show that trimetazidine exerts a pronounced beneficial effect on the ischaemic myocardium without influencing hemodynamic parameters. The mechanism of the cardioprotective activity of the drug is not related to calcium entry blockade or α-adrenoceptor antagonism, but rather caused by a mechanism at a cellular level, so far not known in detail