title: Differential response of DPI-modified cardiac Na+ channels to antiarrhythmic drugs: no flicker blockade by lidocaine.
abstract: Elementary Na+ currents were recorded in cell-attached patches from short-time cultured neonatal cardiocytes in order to test the hypothesis whether the open state of DPI-modified, noninactivating cardiac Na+ channels is basically sensitive to blocking drug molecules such as antiarrhythmics. Lidocaine (300 mumol/liter) effectively reduced the open probability of cardiac Na+ channels and, at a stimulation rate of 1 Hz, depressed the reconstructed macroscopic peak INa to 40 +/- 3.5% of the predrug value. The same drug concentration failed to influence DPI-modified Na+ channels. Their open state proved almost insensitive to lidocaine. tau open decreased only slightly to 85 +/- 2%. Still more importantly, the number of transitions between the conducting and a nonconducting configuration did not increase. At -40 mV, lidocaine may interfere with the open state with an association rate constant of 1.3 x 10(5) mol-1 sec-1 which is about two orders of magnitude smaller than the rate constant obtained with propafenone or prajmalium. Moreover, propafenone (10-20 mumol/liter) or prajmalium (30 mumol/liter) led to a tremendous increase in the number of transitions between the open and a nonconducting configuration. Lidocaine also failed to evoke a fast flicker blockade with reaction kinetics in the microsecond range. It is concluded that DPI-modified cardiac Na+ channels discriminate between lidocaine and other antiarrhythmic drugs. As a tentative explanation, this might be indicative for multiple binding sites for those drugs in cardiac Na+ channels.
authors.affiliation: Physiological Institute, University Freiburg, Germany.
authors.forename: I
authors.initials: I
authors.lastname: Benz
authors.forename: M
authors.initials: M
authors.lastname: Kohlhardt
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D008012:Lidocaine / Q000494:pharmacology*; D009206:Myocardium / Q000378:metabolism*; D010879:Piperazines / Q000494:pharmacology*; D051381:Rats; D015222:Sodium Channels / Q000187:drug effects* / Q000378:metabolism
chemical_list: D010879:Piperazines; D015222:Sodium Channels; C046261:DPI 201-106; D008012:Lidocaine