DUAL EFFECT OF THE LOCAL-ANESTHETIC PENTACAINIDE ON THE NA+ CURRENT OF GUINEA-PIG VENTRICULAR MYOCYTES

1. The effect of the local anaesthetic penticainide (2-alkyl-(4-dialkylamino)-2-pyridyl-butyramide) on macroscopic and single-channel sodium current (I(Na)) of guinea-pig ventricular myocytes was studied with the patch-clamp technique in the cell-attached and inside-out mode. 2. Penticainide (3-60-mu-M) affected the I(Na) from the outside as well as from the cytoplasmic side. 3. Peak I(Na) was reduced by penticainide at concentrations of 6, 30 and 60-mu-M, and this decrease of peak I(Na) was more pronounced when the holding potential was more negative. Despite a reduction of peak I(Na), the time integral of the Na+ current was not changed (60-mu-M) or was even enhanced (6-mu-M), and this enhancement became more pronounced at less negative potentials. 4. At a concentration of 3-mu-M, penticainide increased both the time integral of the current and peak I(Na). 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 I(Na) 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 I(Na) 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 slows the macroscopic inactivation.