Block of single cardiac Na+ channels by antiarrhythmic drugs: The effect of amiodarone, propafenone and diprafenone

Abstract

Cell-attached patch-clamp experiments were performed in cultured cardiocytes of neonatal rats at 19 degrees C to analyze elementary currents through single Na+ channels under control conditions and in the presence of the class 1 antiarrhythmic drugs amiodarone, propafenone, and diprafenone. As observed in a cell-attached patch with only one functioning Na+ channel, repetitive stepping of the membrane at 0.4 Hz triggered periodically channel openings except during a silent period of about 1.5 min. The latter began and ceased abruptly and did not fit the monoexponential distribution of the run length of sweeps without activity (blank sweeps). Treating the cardiocytes with amiodarone, propafenone or diprafenone (10 to 20 mumol/liter) led rapidly to a blockage and reduced the likelihood that membrane depolarization triggers the opening of Na+ channels. The number of blank sweeps increased at the expense of the number of sweeps with activity. The fraction of activity sweeps with superpositions, indicating the simultaneous activation of two or more Na+ channels, also declined. As tested with amiodarone, the run length of blank sweeps is voltage- and time-dependent, analogous to the intensity of the block of macroscopic Na+ currents. Open time, open-time distribution, unitary current size and the tendency to reopen did not differ in unblocked cardiac Na+ channels (i.e. that channel fraction capable of opening in the presence of amiodarone or propafenone) from the respective control values obtained before superfusing the cardiocytes with these drugs. Apart from its blocking action, the propafenone derivative diprafenone exerted additionally a modifying effect and reduced mean open time by up to 45%. In contrast to the block, this reduction in conducting state proved insensitive to changes in holding potential, at least between -130 and -150 mV, the range tested. This means that block was attenuated on hyperpolarization whereas the reduction in open time persisted. It is concluded that, in the presence of these drugs, unblocked cardiac Na+ channels share a number of properties with normal Na+ channels in the absence of these drugs. Shortening of channel lifetime by diprafenone may be indicative of a channel modification brought about possibly by a receptor-mediated facilitation of the transition from the open to the inactivated state.

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

“…This already has been proven in normal cardiac Na + channels with intact inactivation 5 and was further stressed by the present experiments with modified channels. In the presence of 20 /imol/1 propafenone, their unitary conductance was found to be 12 pS in two patches.…”

“…5 Blockade prevents the Na + channel from attaining the conducting configuration while unblocked Na + channels show apparently normal elementary properties, including unitary current size and open-state kinetics. This also implies that plugging and unplugging, the steps that initiate and terminate the channel blockade, remain undetectable even in singlechannel studies.…”

Slowing of the Inactivation of Cardiac Voltage-Dependent Sodium Channels by the Amiodarone Derivative 2-Methyl-3-(3,5-diiodo-4-carboxymethoxybenzyl)benzofuran (KB130015)

“…The effect on the kinetics of I Na inactivation was unex- pected given the known actions of amiodarone, which either does not change the kinetics of fast inactivation (Follmer et al, 1987;Kohlhardt and Fichtner, 1988) or accelerates the decay of late currents (Maltsev et al, 2001). It resembles that of many drugs, including animal or plant toxins, that interact with specific sites on the voltage-dependent Na ϩ channel and modify inactivation (Narahashi, 1996;Catterall, 2000;Goldin, 2001).…”

“…In the present study, we report marked acute effects of KB on the inactivation of Na ϩ channels. These effects were unexpected based on those known for amiodarone (Follmer et al, 1987;Kohlhardt and Fichtner, 1988;Kodama et al, 1999;Maltsev et al, 2001), but a few studies have reported similar effects with high concentrations of thyroid hormones (Craelius et al, 1990;Harris et al, 1991;Dudley and Baumgarten, 1993).…”

Electrophysiological effects of diprafenone, a dimethyl congener of propafenone on guinea‐pig ventricular cells

“…We cannot rule out other possible mechanisms for the different voltage-dependence of the use-dependent sodium channel inhibition with diprafenone and propafenone. For instance, Kohlhardt & Fichtner (1988b) have demonstrated in their cell-attached patch clamp experiments recording single Na' channel currents that diprafenone, unlike propafenone, shortens the lifetime of unblocked channels as an additional effect, apart from its blocking action. Such modification is expected to have a complex influence on the effects of the drug on the net sodium inward current and Vmax of action potential.…”