A Sodium Channel Blocker, Pilsicainide, Produces Atrial Post-Repolarization Refractoriness through the Reduction of Sodium Channel Availability

Abstract

Atrial fibrillation (AF) is the most common tachyarrhythmia. Shortening of atrial action potential duration (APD) and effective refractory period (ERP) is one of the crucial factors in the occurrence and maintenance of AF. ERP is usually shorter than APD, but ERP can be prolonged beyond action potential repolarization in some situations. It is termed as post-repolarization refractoriness (PRR) that is thought to be one of main anti-arrhythmic mechanisms of class I sodium channel blockers (SCBs). Most of anti-arrhythmic agents, including SCBs, have multi-channel blocking effects. It is unknown whether atrial PRR with SCBs is associated with the reduction of sodium channel availability. We therefore explored the relationship between the reduction of sodium channel availability with a pure SCB (pilsicainide or tetrodotoxin) and atrial PRR using the left atrial appendage from male guinea pigs (each group, n = 3~10). Employing a standard microelectrode technique, we evaluated APD measured at 90% repolarization (APD 90 ) and the sodium channel availability, judged from the maximal rate of rise of action potential (Vmax). At a 500-msec basic cycle length (BCL), pilsicainide prolonged atrial ERP assessed by a single extra-stimulus in response to the decrement of the Vmax in a dose-dependent manner without affecting APD 90 . Furthermore, pilsicainide increased the ERP and decreased the Vmax in a rate-dependent manner without APD 90 prolongation at a shorter BCL (200 msec). Importantly, tetrodotoxin reproduced the effects of pilsicainide on atrial ERP, APD 90 , and Vmax. These results indicate that SCBs produce atrial PRR through the reduction of sodium channel availability.

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.…”

“…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. 39 Using a realistic mathematical model, we found that an optimized I Na /I Kr blocker (NCB o /KrB) compared with an optimized I Na blocker alone (NCB o ) increased rate and atrial selectivity, leading to a 4-fold increase in AF-selective I Na block (Figure 3).…”

“…Third, although pilsicainide is an inactivated-state blocker, its experimentally measured time constant is long (28.2±6.2 seconds), reflecting slow unbinding kinetics and limiting its rate selectivity. 32 We used pilsicainide because it is an inactivated-state NCB in clinical use for AF and is more selective for Na + -channel blockade than alternative agents such as vernakalant, ranolazine, flecainide, or propafenone, all of which block K + -channels in the Na + -channel blocking concentration range. It would be interesting to test inactivated-state blockers designed to have faster unbinding kinetics closer to those of the predicted optimal NCBs.…”

A novel anticonvulsant modulates voltage‐gated sodium channel inactivation and prevents kindling‐induced seizures

“…anticonvulsants (Cosford et al 2002;Liu et al 2003;Rogawski and Loscher 2004;Fukuda et al 2011). Many antiepileptic drugs have been developed in the past two decades that modulate the activity of these channels (Rogawski and Loscher 2004), as there is growing evidence that suggests the involvement of abnormal VGSC activity in the pathophysiology of both familial and acquired epilepsy (Meldrum and Rogawski 2007;Zuliani et al 2012).…”

Slow Recovery of Excitability Increases Ventricular Fibrillation Risk as Identified by Emulation

“…These results thus mechanistically explain the good performance of class Ic anti-arrhythmics in terminating atrial fibrillation, but at the cost of increased susceptibility to ventricular arrhythmias. This is for example the case of pilsicainide, a class Ic agent with slow recovery kinetics, successful in the clinical management of atrial fibrillation (Kanki et al, 1998; Fukuda et al, 2011) in spite of reports of its involvement in precipitating ventricular Torsade de Pointes (TdP) arrhythmias and sudden cardiac death (Nakatani et al, 2014), as further corroborated by its “possible risk” TdP category in the CredibleMeds database (Woosley and Romer, 1999). These results also hold for the controversial role of flecainide, another class Ic agent especially successful in the treatment of atrial fibrillation (Wang et al, 1992; Aliot et al, 2011), but with “known risk” TdP category (Woosley and Romer, 1999; Nasser et al, 2015), although its potent inhibition of potassium repolarizing currents can also mediate its pro-arrhythmic profile (Paul et al, 2002; Melgari et al, 2015; Passini et al, 2017).…”