Trimetazidine inhibits Na+,K(+)-ATPase activity, and overdrive hyperpolarization in guinea-pig ventricular muscles

The effect of trimetazidine on Na+,K(+)-ATPase activity or the Na+,K+ pump was studied in guinea pig ventricular muscles with the use of biochemical and electrophysiological methods. The effect of trimetazidine on enzyme activity was compared with that in the liver, jejunum and kidney obtained from the same species. Na+,K(+)-ATPase activity in the heart and liver was significantly and concentration dependently decreased by trimetazidine (above 1.5 x 10(-5) M). Even the highest concentration (1.5 x 10(-4) M) of trimetazidine failed to decrease the Na+,K(+)-ATPase activity in the jejunum and kidney. The membrane potential was recorded in the ventricular muscle with a microelectrode. The hyperpolarization which followed 1-min overdrive stimulation (3.3 Hz) was decreased by trimetazidine (1.5 x 10(-4) M), but the depolarization during the stimulation was not affected by this drug. Ouabain, a potent Na+,K+ pump inhibitor, markedly decreased the overdrive hyperpolarization and increased the depolarization during the stimulation (10(-7), 5 x 10(-7), 10(-6) M). Therefore, the effect of trimetazidine and ouabain on the Na+,K+ pump-mediated alteration in the resting potential is different, suggesting that trimetazidine has additional direct membrane effects, e.g. a decrease in K+ conductance. In conclusion, trimetazidine inhibits Na+,K(+)-ATPase activity and thus the Na+,K+ pump in the ventricular muscles but with an inhibitory effect about 300 times less than that of ouabain. Trimetazidine inhibited the Na+,K(+)-ATPase in the liver as well, but not that in jejunum and kidney.