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The Journal of Membrane Biology

, Volume 139, Issue 3, pp 191–201 | Cite as

Chemically modified cardiac Na+ channels and their sensitivity to antiarrhythmics: Is there a hidden drug receptor?

  • I. Benz
  • M. Kohlhardt
Articles

Abstract

Elementary Na+ currents were recorded at 19°C in inside-out patches from cultured neonatal rat cardiocytes. In analyzing the sensitivity of chemically modified Na+ channels to several class 1 antiarrhythmic drugs, the hypothesis was tested that removal of Na+ inactivation may be accompanied by a distinct responsiveness to these drugs, open channel blockade.

Iodate-modified and trypsin-modified cardiac Na+ channels are noninactivating but strikingly differ from each other by their open state kinetics, a O1–O2 reaction (τopen(1) 1.4±0.3 msec; τopen(2) 5.4±1.1 msec; at −40 mV) in the former and a single open state (τopen 3.0±0.5 msec; at −40 mV) in the latter. Lidocaine (150 μmol/liter) like propafenone (10 μmol/liter), diprafenone (10 μmol/liter) and quinidine (20 μmol/liter) in cytoplasmic concentrations effective to depress NP o significantly can interact with both types of noninactivating Na+ channels to reduce the dwell time in the conducting configuration. lodate-modified Na+ channels became drug sensitive during the O2 state. At −40 mV, for example, lidocaine reduced τopen(2) to 62±5% of the control without detectable changes in τopen(1). No evidence could be obtained that these inhibitory molecules would flicker-block the open Na+ pore. Drug-induced shortening of the open state, thus, is indicative for a distinct mode of drug action, namely interference with the gating process. Lidocaine proved less effective to reduce τopen(2) when compared with the action of diprafenone. Both drugs apparently interacted with individual association rate constants, alidocaine was 0.64×106 mol−1 sec−1 and adiprafenone 13.6×106 mol−1 sec−1. Trypsin-modified Na+ channels also appear capable of discriminating among these antiarrhythmics, the ratio adiprafenone/alidocaine even exceeded the value in iodate-modified Na+ channels. Obviously, this antiarrhythmic drug interaction with chemically modified Na+ channels is receptor mediated: drug occupation of such a hypothetical hidden receptor that is not available in normal Na+ channels may facilitate the exit from the open state.

Key words

Single noninactivating Na+ channels Iodate Trypsin (−)-DPI 201-106 Drug-sensitive open state Channel-associated binding sites 

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Copyright information

© Springer-Verlag New York Inc. 1994

Authors and Affiliations

  • I. Benz
    • 1
  • M. Kohlhardt
    • 1
  1. 1.Physiological Institute of the University of FreiburgFreiburg/Br.Germany

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