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Laboratorium voor Fysiologie KUL, Leuven, Belgium.

1. The effect of the local anaesthetic penticainide (2-alkyl-(4-dialkylamino)-2-pyridyl-butyramide) on macroscopic and single-channel sodium current (INa) of guinea-pig ventricular myocytes was studied with the patch-clamp technique in the cell-attached and inside-out mode. 2. Penticainide (3-60 microM) affected the INa from the outside as well as from the cytoplasmic side. 3. Peak INa was reduced by penticainide at concentrations of 6, 30 and 60 microM, and this decrease of peak INa was more pronounced when the holding potential was more negative. Despite a reduction of peak INa, the time integral of the Na+ current was not changed (60 microM) or was even enhanced (6 microM), and this enhancement became more pronounced at less negative potentials. 4. At a concentration of 3 microM, penticainide increased both the time integral of the current and peak INa. 5. The shape of the steady-state current-voltage relationship and the steady-state inactivation curve were not influenced by penticainide. 6. In pronase-modified inside-out patches penticainide reduced INa at the beginning of a depolarizing pulse to the same extent as at the end (400 ms), indicating a very fast blockade of the bursting Na+ channel. The most prominent effects on pronase-modified single-channel INa were an increase of sweeps without activity, and a fast, repeatedly occurring block (flickering) of the bursting Na+ channel. 7. The amplitude of the unitary current was not altered. 8. It is concluded that penticainide blocks the open Na+ channel, and in addition shows the macroscopic inactivation.