title: On the mechanism of drug-induced blockade of Na+ currents: interaction of antiarrhythmic compounds with DPI-modified single cardiac Na+ channels.
abstract: In patch-clamped membranes from neonatal rat cardiocytes, elementary Na+ currents were recorded at 19 degrees C for study of the inhibitory influence of several antiarrhythmic drugs including lidocaine, diprafenone, propafenone, and prajmalium on DPI-modified cardiac Na+ channels. Diprafenone (20 mumol/l) and lidocaine (300 mumol/l) induced a voltage- and time-dependent block of reconstructed macroscopic sodium current (INa). The drugs depressed the sustained, noninactivating INa component (which reflects the number and open probability of DPI-modified Na+ channels) effectively, in a voltage- and time-dependent fashion. Once opened, DPI-modified Na+ channels are highly drug-sensitive. Antiarrhythmic drugs (propafenone, diprafenone, and, to a lesser extent, lidocaine) provoke a flicker block, that is, the long-lasting openings are chopped into a large number of short and grouped openings. This indicates rapid transitions between a drug-associated, blocked state and a drug-free, conducting state. The latter has a unitary conductance of 12 pS, very similar to the control value in the absence of antiarrhythmic drugs. The decrease in open time of drug-treated DPI-modified Na+ channels is concentration-dependent. Hill coefficients for propafenone of about 1.0 and for prajmalium of about 0.7 were calculated. A blocking rate constant of 6.1 x 10(7) mol-1sec-1 for propafenone, but of 1.5 x 10(7) mol-1sec-1 for prajmalium was obtained at -30 mV. The unblocking rate constant for propafenone was, also at -30 mV, about twice as large as the unblocking rate constant for prajmalium. The open channel block kinetics are essentially voltage-dependent. The affinity of the channel-associated drug receptor increases on membrane depolarization. The blocking rate constant was inversely related to the number of Na+ ions moving through the open channel. It is concluded that the manifestation of this voltage- and Na+-dependent flicker block is intimately related to removal of fast Na+ inactivation.
authors.affiliation: Physiological Institute of the University Freiburg, Federal Republic of Germany.
authors.forename: M
authors.initials: M
authors.lastname: Kohlhardt
authors.forename: H
authors.initials: H
authors.lastname: Fichtner
authors.forename: U
authors.initials: U
authors.lastname: Fröbe
authors.forename: J W
authors.initials: JW
authors.lastname: Herzig
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D002395:Catecholamines / Q000494:pharmacology*; D002478:Cells, Cultured; D048288:Imidazolines; D008012:Lidocaine / Q000494:pharmacology; D009206:Myocardium / Q000166:cytology* / Q000378:metabolism; D011219:Prajmaline / Q000494:pharmacology; D011405:Propafenone / Q000031:analogs & derivatives / Q000494:pharmacology; D051381:Rats; D012964:Sodium / Q000378:metabolism* / Q000502:physiology; D015222:Sodium Channels / Q000187:drug effects*
chemical_list: D000889:Anti-Arrhythmia Agents; D002395:Catecholamines; D048288:Imidazolines; D015222:Sodium Channels; C047546:diprafenone; D011405:Propafenone; D011219:Prajmaline; D008012:Lidocaine; D012964:Sodium; C011775:(3,4-dihydroxyphenylamino)-2-imidazoline