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

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.