prajmaline and diprafenone

Elementary Na+ currents were recorded at 19 degrees 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 (tau open(1) 1.4 +/- 0.3 msec; tau open(2) 5.4 +/- 1.1 msec; at -40 mV) in the former and a single open state (tau open 3.0 +/- 0.5 msec; at -40 mV) in the latter. Lidocaine (150 mumol/liter) like propafenone (10 mumol/liter), diprafenone (10 mumol/liter) and quinidine (20 mumol/liter) in cytoplasmic concentrations effective to depress NPo significantly can interact with both types of noninactivating Na+ channels to reduce the dwell time in the conducting configuration. Iodate-modified Na+ channels became drug sensitive during the O2 state. At -40 mV, for example, lidocaine reduced tau open(2) to 62 +/- 5% of the control without detectable changes in tau open(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 tau open(2) when compared with the action of diprafenone. Both drugs apparently interacted with individual association rate constants, a(lidocaine) was 0.64 x 10(6) mol-1 sec-1 and a(diprafenone) 13.6 x 10(6) mol-1 sec-1. Trypsin-modified Na+ channels also appear capable of discriminating among these antiarrhythmics, the ratio a(diprafenone)/a(lidocaine) 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.

Topics: Animals; Anti-Arrhythmia Agents; Biological Transport; Cells, Cultured; Iodates; Lidocaine; Myocardium; Prajmaline; Propafenone; Quinidine; Rats; Receptors, Drug; Sodium Channels; Trypsin

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.

Topics: Animals; Anti-Arrhythmia Agents; Catecholamines; Cells, Cultured; Imidazolines; Lidocaine; Myocardium; Prajmaline; Propafenone; Rats; Sodium; Sodium Channels