AIM: To make a LQT(3) model (one form of the long QT syndromes) and to investigate the effect of mexiletine on LQT(3). METHODS: Sea anemone toxin (ATX 11) was used to produce the LQT(3) model. The Effect of mexiletine on LQT(3) was performed on single Na channel, action potential, and electrocardiography in guinea pigs. RESULTS: With the binding of ATX 11 to the Na(+) channels, the probability of being in the open state and the open time constant of single Na(+) channel with long opening mode increased significantly. Action potential duration APD(50), APD(90), and the maximal upstroke velocity of phase 0 were increased by 25.8%, 26.1%, and 12%, respectively. The QT interval and QTc, a rectified QT interval, increased by 12.8% and 16.9%. On the contrary, after application of mexiletine, the open probability of single Na+ channel was reduced greatly. In the presence of ATX 11 (40 nmol/L), mexiletine (1, 5, 15, 45, 70 mumol/L) shortened the APD(50) by 0.5%, 6.7%, 14.4%, 19.4%, and 18.8%, respectively, and decreased the APD(90) and V(max) accordingly. In the experiments with ECG, mexiletine reversed the ATX II-produced prolongation effects on QTc in a dose-dependent manner. CONCLUSION: Mexiletine may be an effective drug in the treatment of LQT(3).