Modification of single cardiac Na+ channels by DPI 201-106

Kohlhardt, M.; Fröbe, U.; Herzig, J. W.

doi:10.1007/bf01869712

Cited by 87 publications

(50 citation statements)

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“…Use of diphenylpiperazinylindole derivative DPI 201-106 as a kinetic modifier that removes fast inactivation in cardiac Na + channels 7 in this study showed that propafenone, its derivative diprafenone, prajmalium, or lidocaine may interact with open, noninactivating Na + channels. The resultant voltage-and Na + -dependent flicker block shares many properties with the flicker block evoked by a great variety of blocking molecules in ionic channels such as Cl" or K + channels that are intrinsically devoid of fast inactivation.…”

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confidence: 68%

On the mechanism of drug-induced blockade of Na+ currents: interaction of antiarrhythmic compounds with DPI-modified single cardiac Na+ channels.

Kohlhardt

Fichtner

Fröbe

et al. 1989

Circulation Research

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In patch-clamped membranes from neonatal rat cardiocytes, elementary Na + currents were recorded at 19° C for study of the inhibitory influence of several antiarrhythmic drugs including lidocaine, diprafenone, propafenone, and prajmalium on DPI-modified cardiac Na L ocal anesthetics and related antiarrhythmic drugs compose a structurally heterogeneous group of organic compounds capable of interacting with Na + channels in excitable membranes, including cardiac cells. Several lines of evidence strongly support the assumption that a channel-associated binding site exists 1 -3 whose interaction or binding with these drugs will finally block the channel and hinder sodium ions from passing through the pore. The resultant decrease in excitability may be an antiarrhythmic principle in heart From the Physiological Institute of the University Freiburg Freiburg/Br., Federal Republic of Germany.Supported by a grant of the Deutsche Forschungsgemeinschaft (Ko 778/2-1), Bonn, Federal Republic of Germany.Address for correspondence: Professor Dr. M. Kohlhardt, Physiological Institute of the University, Hermann-Herder-Str. 7, D-78 Freiburg/Br., Federal Republic of Germany.Received January 20, 1988; accepted September 28, 1988. to suppress irregular impulses. The remarkably different manifestation of Na + current depression, which attracted considerable theoretical interest and was well documented in numerous biophysical studies during the past years, reflects the combined influence of such factors as voltage, driving rate, and drug hydrophobicity in determination of the strength of blockade of Na + currents. The rather complex block phenomenology finds elegant and conclusive explanations by the models of Hille 2 and Hondeghem and Katzung 3 on the one hand and Starmer et al< on the other hand. The HilleHondeghem-Katzung model postulates a modulated receptor whose drug affinity depends on the channel state, rested or activated/inactivated, while the Starmer model assumes a guarded receptor, that is, drug access is controlled by the channel state. Such modeling of block proved valuable and indispensable in the understanding of some elementary properties of voltage-dependent Na + channels.by guest on May 12, 2018

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confidence: 68%

On the mechanism of drug-induced blockade of Na+ currents: interaction of antiarrhythmic compounds with DPI-modified single cardiac Na+ channels.

Kohlhardt

Fichtner

Fröbe

et al. 1989

Circulation Research

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“…Ouabain-sensitive 16Rb uptake into human red blood cells was measured essentially as described by Young & Ellory (1982) (Buggisch et al, 1985) consistent with a persistent open state ofthe Na' channel (Kohlhardt et al, 1986); (ii) Sensitization of myocardial contractile proteins to Ca2" ; and (iii) Inhibition of the Na' pump (this paper). Binding of DPI 201-106 to the ventricular Na' channel prolongs the action potential (Buggisch et al, 1985) with a concentration-dependence similar to that found by us for the positive inotropic effects, suggesting a close link.…”

Section: Methodsmentioning

confidence: 95%

Inhibition of the sodium pump by cardioactive DPI 201‐106

Kaumann¹,

Richards

Russell³

1987

British J Pharmacology

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“…Furthermore, Penticainide has some unique physico-chemical properties, being positively charged at a pH 7x4 (pKa = 10 0) and having a very low lipophilicity (partition coefficient = 0 35) as compared to the best-studied local anaesthetic lidocaine (partition coefficient = 249; Broughton, Grant, Starmer, Klinger, Stambler & Strauss, 1984). To be able to analyse a large number of single-channel events with a reasonable time resolution, we decided to use the novel cardiotonic compound DPI 201-106 as a tool to slow the fast entrance of the normal cardiac Na+ channel into the absorbing state that results in a voltagedependent prolongation of the mean open time (Kohlhardt, Frobe & Herzig, 1986, 1987Nilius, Benndorf, Markwardt & Franke, 1987 b). DPI has the further advantage that it does not change properties of the open Na+ channel .…”

Section: Introductionmentioning

confidence: 99%

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

Carmeliet¹,

Nilius²,

Vereecke³

1989

The Journal of Physiology

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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.

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Modification of single cardiac Na+ channels by DPI 201-106

Cited by 87 publications

References 37 publications

On the mechanism of drug-induced blockade of Na+ currents: interaction of antiarrhythmic compounds with DPI-modified single cardiac Na+ channels.

On the mechanism of drug-induced blockade of Na+ currents: interaction of antiarrhythmic compounds with DPI-modified single cardiac Na+ channels.

Inhibition of the sodium pump by cardioactive DPI 201‐106

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

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