No abstract

Delayed afterdepolarizations have been described to occur during reperfusion after ischemia; it is the oscillatory uptake and release of Ca 2+ from the sarcoplasmic reticulum that underlies the phenomenon [1-2]; oscillations of intracellular Ca z+ concentration are accompanied by fluctuation of membrane current and mechanical activity.The tested hypothesis was that trimetazidine might be antiarrhythmic by • decreasing or inhibiting the formation of DADs • use-dependent blockade of the sodium current Papillary muscles were obtained from the right ventricle of guinea pigs (120-350 g). The hearts were removed within 1 minute after cervical dislocation and placed in cold (4°C) modified Tyrode's solution. Papillary muscle (< 1.0 × 0.5 mm) preparations were allowed to recover for at least 45 minutes before any recording was commenced. The temperature was 37°C throughout the experiment, and the pH was 7.4 when bubbled with 5% CO2 and 95% 02.Action potentials were recorded from the surface cells of the preparation using intracellular glass microelectrodes filled with 3 M KC1. The action potential was elicited by delivering rectangular pulses of 0.5-to 1-ms duration and an amptitude of 150% threshold applied to the preparation through a thin (0.l-ram) platinum wire. Action potential recordings were photographed directly from the oscilloscope screen. The drug was directly added to the Tyrode's solution just before use.Statistical analysis was done using the Fisher exact test or the paired Student's t test at the 1% level of significance. Effect of the trimetazidine on DADs of guinea-pig papillary muscle10-4 M trimetazidine had no appreciable effect on DADs, but 10 -3 M suppressed DADs. In both cases, the rate of stimulation was 5 Hz. Evaluation of the use-dependent blockade by trimetazidine on the action potential Vm~A train of stimuli at 6.7 Hz in the presence of 10 G M trimetazidine showed only a minimal inhibition of Vm~x (12%), but there was no use dependence. There was more blocking effect of 10 -~ M TMZ on V,~ax ( -33%) when the stimulation rate was 6.7 Hz than when it was 3. Hz. A very pronounced blockage by 10-3 M TMZ occurred at a stimulation rate of 3 Hz. Blocking effect of trimetazidine I0 3 MA plot of the percentage of the first pulse versus pulse number showed the blocking effect of trimetazidine (10 :~ M) on Vm~x of the action potential while stimulating the preparation at a frequency of 4 Hz. Conclusion 1. Delayed afterdepolarizations occur during reperfusion after ischemia. Trimetazidine (10 -:~ M) decreased the amplitude of the DADs and should have antiarrhythmic properties against these types of arrhythmias. Trimetazidine 10 .4 M did not change the amplitude of the DADs. 2. Trimetazidine caused V~x to decrease without major changes in membrane potential, indicating that trimetazidine has a direct effect on the sodium current. The effect of trimetazidine (> 10 -(; M) on the sodium current was dependent on the frequency of stimulation, indicating that the blockade of the sodium current by trimetazidine show...

Angiotensin-converting enzyme (ACE) inhibitors protect the myocardium from experimental lethal ventricular arrhythmias induced by ischemia or reperfusion. Hypothetically, such arrhythmias may result from the calcium-dependent transient inward current Iti. It is already known that perindoprilat decreased the transient inward current in guinea-pig myocytes [1]. In the same preparation, however, angiotensin-II decreased the transient inward current, an effect opposite to that required to prove that the ACE inhibitor exerted its beneficial effects on Iti by lessening the action of angiotensin-II. We, therefore, selected another species, the rabbit, in which angiotensin-II was known to have a positive inotropic effect. Perindoprilat (1 microM but not 0.01 microM) decreased the transient inward current from -8.93 +/- 0.80 microA/cm2 to -5.33 +/- 0.74 microA/cm2 (p < 0.05). Perindoprilat (1 microM) also protected from the effects of angiotensin-II (0.01 and 0.1 microM), which on its own increased the amplitude of the transient inward current. Based on our results, we conclude that perindoprilat (1 microM) prevents the effect of angiotensin-II in promoting the transient inward current in the rabbit. Hence our data support the hypothesis that the ACE inhibitor, perindoprilat, might in relatively high concentrations have an antiarrhythmic effect, at least in part through inhibition of angiotensin-II-evoked calcium-dependent Iti.