Electrophysiological effects of the combination of mexiletine and flecainide in guinea‐pig ventricular fibres

Abstract

1 The effects of flecainide alone, mexiletine alone and their combination at the Na+ channel level were studied in guinea-pig papillary muscles. The maximum upstroke velocity (V.ax) was used as an indirect index of the magnitude of the fast inward Na+ current (INa).2 In muscles driven at 0.02 Hz, neither mexiletine (10-M) nor flecainide (10-6 M) nor the combination of both drugs modified the action potential characteristics. Mexiletine, but not flecainide, increased the effective refractory period/action potential duration ratio; this enhancement was greater when flecainide was also present.3 Mexiletine or flecainide alone produced a frequency-dependent V.., block. Although at 0.5 Hz the blockade induced by the combination of flecainide and mexiletine was similar to that produced by flecainide alone, in muscles driven at 1 and 2 Hz the combination increased the magnitude and the onset rate of the Vmax block.4 The time constant of recovery of V.ax block was similar in the presence of flecainide or the combination mexiletine plus flecainide (Tre = 16.4 + 2.3 s and 16.7 + 2.7s, respectively), but the combination decreased the magnitude of the slow component of reactivation induced by flecainide (93.8 + 1.5% versus 68.9 + 1.7%). Moreover, the combination of both drugs was more effective in inhibiting the V,,.. of early test stimuli than either drug alone. 5 It is concluded that the combination of mexiletine and flecainide is synergistic at driving rates faster than 0.5 Hz without detracting from the characteristics of flecainide.

Effects of flecainide on isolated vascular smooth muscles of rat

“…Flecainide acetate is a class Ic antiarrhythmic drug effective both in experimental and clinical ventricular and supraventricular tachyarrhythmias (Anderson et al, 1981;Duff et al, 1981;Campbell, 1983a;Hellestrand et al, 1984;Holmes & Heel, 1985;Somberg & Tepper, 1986). In cardiac muscle fibres, flecainide exhibits both very slow onset kinetics and recovery from V.ax block (Campbell & Vaughan Williams, 1983;Campbell, 1983a,b;Delpon et al, 1991) due to its high affinity for the activated and inactivated states of the Na channels (Anno & Hondeghem, 1990).…”

“…In cardiac muscle fibres, flecainide exhibits both very slow onset kinetics and recovery from V.ax block (Campbell & Vaughan Williams, 1983;Campbell, 1983a,b;Delpon et al, 1991) due to its high affinity for the activated and inactivated states of the Na channels (Anno & Hondeghem, 1990). …”

The mode of action of several opioids on cardiac muscle

“…The main effect was depression of action potential 1'max. Vmax is a qualitative index of Na+ conductance, and has been widely used as an indicator of Na+ channel activity with class I antiarrhythmic agents or other local anaesthetics (Carmeliet, Morad, Heyden & Vereecke, 1986;Delpon, Valenzuela & Tamargo, 1991). Thus these opioids could reduce the Na+ channel activity of cardiac cells and the data suggest that dextropropoxyphene, norpropoxyphene, methadone and pentazocine have an effect at least as strong as quinidine; pethidine was less potent.…”

Effects of lisinopril on electromechanical properties and membrane currents in guinea‐pig cardiac preparations

“…The microelectrode was connected via Ag-AgCl half-cell to a high impedance, capacity neutralizing amplifier (WPI model 701). The maximum rate of depolarization (Vm..) of the action potential was obtained by electronic differentiation (Valenzuela et al, 1988;Delpon et al, 1989;1991b). The differentiator used had an upper limit of linearity of 1000 V s-' and possessed variable input filters (3 Hz-260 Hz).…”