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

Abstract

SUMMARY1. The blocking mechanism of a disopyramide 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 in concentrations between 3 and 100 /SM.The S-enantiomer of DPI 201-106 (5 /tM) was used as a tool to slow the inactivation, 2. When in cell-attached or inside-out patch experiments up to 100 /SMPenticainide 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 ,tM-Penticainide in the pipette, the open-state probability of the Na+ channel was much lower than in the absence of 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 singlechannel 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 openings 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.

Use‐dependent block of Na+ currents by mexiletine at the single channel level in guinea‐pig ventricular myocytes

“…Previous studies of Na+ channel block by class I agents showed a reduction in open channel probability (P.) without change in single channel conductance (Nilius et al, 1987;Kohlhardt & Fichtner, 1988;Carmeliet et al, 1989;Grant et al, 1989;McDonald et al, 1989;Undrovinas et al, 1989;Baumgarten et al, 1991;Gruber et al, 1991). We also observed this change for mexiletine.…”

“…However, we could not detect any significant change in the mean open time during the train. A shortening of mean open time has been reported for diprafenone (Kohlhardt & Fichtner, 1988) and penticainide (Carmeliet et al, 1989;Gruber et al, 1991) having a high affinity for the activated state of the channel. On the other hand, there is a conflict among the reports as to lignocaine having a high affinity for the inactivated state of the channel.…”

“…Recently, Undrovinas et al (1989) and Baumgarten et al (1991) observed usedependent block of single channel currents from frequencydependent effects or the difference between initial and the final segments of successive depolarizations. Similarly, the use-dependence of the blocking action of the drug was presented in DPI 201-106 modified Na+ channels (Carmeliet et al, 1989). All of the above reports, however, did not mention the appearance and extent of the voltage shifts occurring during the drug exposure, and how much the voltage shift effects affected the observed use-dependent block.…”

“…Recordings of single Na4 channel currents have provided direct information on the mechanism by block by class I antiarrhythmic agents (Nilius et al, 1987;Kohlhardt & Fichtner, 1988;Grant et al, 1989;McDonald et al, 1989;Undrovinas et al, 1989) and on the drug binding site in cardiac Na4 channels (Carmeliet et al, 1989;Baumgarten et al, 1991;Gruber et al, 1991). The class I agents are also characterized by use-dependent block of INa.…”

Modes of the Na Channel Blocking Action of Pilsicainide, a New Antiarrhythmic Agent, in Cardiac Cells.

“…Recently, Carmeliet et al (4) have reported that a local anesthetic, penticainide, which is positively charged at pH 7.4 (pKa = 10.0), ex erted a block of cardiac Na channels when it was applied to the outer side of the cardiac cell membrane, while no significant block was observed by application of the drug to the in ner side of the S-DPI 201-106 (which is known to slow Na channel inactivation) treated car diac cell membrane. On the other hand, these authors found that penticainide reduced INa by acting from the outside as well as from the cytoplasmic side of the Na channels in untreat ed guinea pig ventricular myocytes (5).…”