Interactions of flecainide with guinea pig cardiac sodium channels. Importance of activation unblocking to the voltage dependence of recovery.

Abstract

Effects of flecainide, a potent antiarrhythmic agent, on sodium channel availability was investigated in guinea pig single cardiac cells by the whole-cell voltage-clamp technique.Sodium current (INa) experiments were performed at 170 C, and maximum upstroke velocity (Vmax) experiments were performed at 370 C. Flecainide (3 ,M) caused little tonic block, but reduced sodium channel availability in a use-dependent manner. The latter effect was accentuated by depolarization and attenuated by hyperpolarization. Long (200-msec) and short (10-msec) depolarizations yielded similar use-dependent block. These results indicate that flecainide has a low affinity for rested (R) and inactivated (I) channels but a high affinity for activated ones (A). In each of these states, the channels can bind to drug to form the corresponding RD, ID, and AD states. Recovery from flecainide block consisted of two components. An initial fast component was strongly voltage dependent: with increasing hyperpolarization, recovery developed more quickly and to a larger extent. At 170 C, the mean time constant shortened from 132±81.6 msec at -120 mV to 46.9±34.1 msec at ±160 mV (kinetics were too fast for accurate measurement at 370 C). A later slow component was largely voltage independent: at 370 C, the mean time constant was 9.8±3.2 seconds at -100 mV and 10.7±3.8 seconds at -75 mV. The slow component of recovery was similarly independent of voltage at 170 C. In terms of the modulated-receptor theory, our results indicate that the fast recovery depends on availability for unblocking (RD) but occurs during activation (AD>A).Indeed, when the RD state is maximized by strong hyperpolarization, activation unblock was also maximized. However, during depolarization to -100 mV, availability for activation unblock declined with a time constant of 98±12 msec (RD=RID). Therefore, the voltage-dependent fast unblocking is mostly due to priming of the RD state (RD B=ID), and the voltage-independent slow unblock reflects dissociation of flecainide from closed states (RD=>R and ID=1). We conclude that flecainide interacts with sodium channels preferentially in the activated state, whereas unblocking occurs via two separate pathways: activated and closed states. Furthermore, drug association with channels shifts the voltage dependence of closed-state transitions (RD<ID) and their kinetics toward more negative potentials. (Circulation Research 1990;66:789-803) Flecainide is a potent antiarrhythmic agent that blocks cardiac sodium channels in a timeand voltage-dependent fashion: reduction of maximum upstroke velocity (Vma)

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

“…In fact, like the present data for diprafenone, the extent of use-dependent block of ,.,< of INa with penticainide, disopyramide and flecainide was shown to be attenuated by hyperpolarization, while enhanced by depolarization of membrane potential within the range of -90 to -70 mV (Carmeliet, 1988;Gruber & Carmeliet, 1989;Anno & Hondeghem, 1990).…”

“…Dissociation (unbinding) of drugs from the sodium channels during the activated state (activation unblock) is enhanced by hyperpolarization of the resting membrane potential (Anno & Hondeghem, 1990), leading to an attenuation of the extent of block during the stimulation trains. In fact, like the present data for diprafenone, the extent of use-dependent block of ,.,< of INa with penticainide, disopyramide and flecainide was shown to be attenuated by hyperpolarization, while enhanced by depolarization of membrane potential within the range of -90 to -70 mV (Carmeliet, 1988;Gruber & Carmeliet, 1989;Anno & Hondeghem, 1990).…”

Electrophysiological effects of SD‐3212, a new antiarrhythmic agent with vasodilator action, on guinea‐pig ventricular cells

“…The temperature was maintained at 35C. Following the increase in calcium concentration of the medium to 1.8 (Anno & Hondeghem, 1990). Details of the clamp pulse protocols are given in the results section.…”

Antiarrhythmic Medications for Cardioversion and Maintenance of Sinus Rhythm in Patients with Cardiac Arrhythmias: A Review of the Literature

“…The mechanism of action is blockade of the cardiac fast inward Na current, INa, and the rapid component of the delayed rectifier K + , IKr, current [41]. Flecainide undergoes extensive hepatic biotransformation via cytochrome P450 CYP2D6 with inactive metabolites, making up about 85%, excreted by the urine.…”