Modes of the Na Channel Blocking Action of Pilsicainide, a New Antiarrhythmic Agent, in Cardiac Cells.

Abstract

Using a whole cell clamp technique, the blockade of sodium currents (INa) by pilsicainide, a new antiarrhythmic agent, applied either intracellularly or extra cellularly, was studied in single myocytes isolated from guinea pig right ventricle. Pilsicainide applied extracellularly inhibited the peak amplitude of INa in concentration (from 105 M to 104 M) and rate (from 0.5 Hz to 3.0 Hz) dependent manners. The onset rate of the blockade in INa was almost constant, independent of frequency of stimulus, but higher at high concentration of pilsicainide. The time con stant in the recovery phase from INa inactivation remained almost constant (65 to 75 msec) in the range of concentrations used. Similar results were obtained by intracellu lar application of 10-3 M pilsicainide. Pilsicainide applied intracellularly inhibited INa in a rate-dependent manner. The blocking potency of internally applied pilsicainide almost corresponded to that of external 10-5 M pilsicainide. The onset rate of INa in activation (from 0.098/pulse to 0.130/pulse) and the recovery time constant (77 msec) was similar to those of external 10-5 M pilsicainide. These results suggest that pilsi cainide, irrespective of intra or extracellular application, shares a common binding site to block INa in cardiac myocytes.

Potassium Channel Blockade Enhances Atrial Fibrillation–Selective Antiarrhythmic Effects of Optimized State-Dependent Sodium Channel Blockade

“…In rabbit atrial cardiomyocytes at therapeutic concentrations (<3 μmol/L), pilsicainide has no effect on the APD, the voltage-dependent Ca 2+ current, the delayed-rectifier K + current, and the inward-rectifier K + current, highlighting its selectivity for the Na + channel at the concentration used here (2 μmol/L). 31 In our experiments, pilsicainide decreased atrial and ventricular Na + -dependent parameters in a rate-dependent manner with little effect on APD, consistent with previous animal studies in guinea pig, [32][33][34][35] dog right atrium and pulmonary vein, 36,37 and rat right ventricle. 32,36 The addition of dofetilide significantly prolonged APD in atrial and ventricular cardiomyocytes, in agreement with previous work in canine right and left atrium 30 and ventricle 38 and guinea pig atria.…”

Long-Term Prognosis of Probands With Brugada-Pattern ST-Elevation in Leads V 1 –V 3

“…8,10,11 Baseline electrophysiological studies (EPS) were performed in 232 (70%) patients. A maximum of 3 ventricular extrastimuli were delivered from 2 right ventricular (RV) sites (RV apex and RV outflow tract) unless VF or polymorphic ventricular tachycardia (VT) (lasting Ն10 beats) that terminated spontaneously within 30 seconds, causing syncope, or requiring intervention to be terminated was elicited at a previous step.…”

Profiles of Aprindine, Cibenzoline, Pilsicainide and Pirmenol in the Framework of the Sicilian Gambit

“…71,76 Inhibition of iNa by pilsicainide included both tonic (resting) and phasic (use-dependent) components with greater use-dependent block of higher depolarization pulse frequencies. 71,[76][77][78] Recovery of iNa in the presence of pilsicainide (10-30 mol/ L) followed a double exponential function, most likely reflecting rapid recovery of drug-free Na + channels and slow recovery of drug-associated channels with time constants from 15 to 70 ms and 65-580 ms, respectively. 71,[76][77][78] Inomata et al investigated the state-dependence of sodium channel blockade in guinea pig atrial myocytes pretreated with scorpion toxin (5 mol/L), which inhibits inactivation of iNa.…”

“…71,[76][77][78] Recovery of iNa in the presence of pilsicainide (10-30 mol/ L) followed a double exponential function, most likely reflecting rapid recovery of drug-free Na + channels and slow recovery of drug-associated channels with time constants from 15 to 70 ms and 65-580 ms, respectively. 71,[76][77][78] Inomata et al investigated the state-dependence of sodium channel blockade in guinea pig atrial myocytes pretreated with scorpion toxin (5 mol/L), which inhibits inactivation of iNa. 77 Application of pilsicainide (10 mol/L) to these myocytes resulted in a use-dependent decrease in the peak amplitude of the relatively persistent iNa, and this iNa inhibition was associated with an accelerated phase current decay.…”

“…71,[76][77][78] Pilsicainide reduced iNa elicited by depolarization pulses (0.1-0.2 Hz) in a concentration-dependent manner with an IC50 of 20-30 mol/L. 71,76 Inhibition of iNa by pilsicainide included both tonic (resting) and phasic (use-dependent) components with greater use-dependent block of higher depolarization pulse frequencies.…”