Properties of the block of single Na+ channels in guinea‐pig ventricular myocytes by the local anaesthetic penticainide.

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Abstract
1. The blocking mechanism of a disopramide derivative Penticainide (2-alkyl-(4-(dialkylamino)-2)pyridyl-butyramide) on cardiac Na+ channels has been studied using single-channel analysis in cell-attached and inside-out patches from guinea-pig ventricular cells. Penticainide was applied on concentrations between 3 and 100 .mu.M. The S-enantiomer of DPI 201-106 (5 .mu.M) was used as a tool to slow the inactivation, improve the time resolution by prolonging the mean open time, and to increase the number of openings per depolarization of the channel. 2. When in cell-attached or inside-out patch experiments up to 100 .mu.M Penticainide was applied to the bathing solution no significant effect was observed on the probability of the channel being open or on the mean open time. 3. In cell-attached patch experiments with 100 .mu.M-Penticainide in the pepette, the open-state probability of the Penticainide. No significant changes were found in the potential of half-maximum activation or in the slope of the activation curve. The maximum open-state probability was reduced by a factor five in the presence of Penticainide. The single-channel conductance was not affected by the drug. 4. The decrease in the probability of the channel being open was mainly due to an increased probability of observing sweeps with no activity (''nulls''). 5. A dramatic relief from the block was observed when pauses were interposed into the normal activation pattern, or when the pacing rate was reduced. 6, The distribution of the open times of the bursting Na+ channel could be fitted with two exponentials. Penticainide in the patch pipette reduced the mean open time. Also the contribution of the number of long openings to the total number of opening was reduced. 7. Closed-time distribution was also fitted with two exponentials. Penticainide in the patch pipette prolonged the long mean closed time. The contribution of the number of short closings to the total number of closings was decreased. 8. Penticaindide in the patch pipette did not significantly change the time constant of the decay of the ensemble-averaged currents measured at -30 mV. Because of the close correlation between the burst duration and the time constant of inactivation (Nilius, Vereecke and Carmeliet, 1988b), we conclude that no striking effect of Penticainide on the burst duration can be expected. 9. The shortening of the mean opentime, and the prolongation of the closed time between individual openings when Penticainide is applied from the outside of the channel, can be described by a simple block of the open channel by extracellular Penticainide with a blocking rate of 3 .cntdot. 74 .times. 106 M-1s-1 and an unblocking rate of 286 s-1, resulting in an apparent Kd value of 76 .cntdot. 6 .mu.M, in close agreement with data obtained from multicellular preparations (Carmeliet, 1988).