Atrial-Selective Sodium Channel Block Strategy to Suppress Atrial Fibrillation: Ranolazine versus Propafenone

Abstract

Ranolazine has been shown to produce atrial-selective depression of sodium channel-dependent parameters and suppress atrial fibrillation (AF) in a variety of experimental models. The present study contrasts the effects of ranolazine and those of a clinically used anti-AF class IC agent, propafenone. Electrophysiological and anti-AF effects of propafenone and ranolazine were compared at clinically relevant concentrations (i.e., 0.3-1.5 and 1-10 M, respectively) in canine isolated coronaryperfused atrial and ventricular preparations. Transmembrane action potential and pseudo-ECG were recorded. Both ranolazine and propafenone produced atrial-selective prolongation of action potential duration. Propafenone depressed sodium channel-mediated parameters [maximum rate of rise of the action potential upstroke (V max ), conduction time, and diastolic threshold of excitation] and induced postrepolarization refractoriness to a greater degree than ranolazine, and these effects, unlike those induced by ranolazine, were not or only mildly atrial-selective at normal rates (cycle length 500 ms). At fast pacing rates, however, the effects of propafenone on V max and conduction time became atrial-selective, because of the elimination of diastolic interval in atria, but not in ventricles. Propafenone (1.5 M) and ranolazine (10.0 M) were effective in preventing the initiation of persistent acetylcholine-mediated AF (6/7 and 9/11 atria, respectively), its termination (8/10 and 8/12 atria, respectively), and subsequent reinduction (8/8 and 7/8 atria, respectively). Thus, propafenone and ranolazine both suppress AF, but ranolazine, unlike propafenone, does it with minimal effects on ventricular myocardium, suggesting a reduced potential for promoting ventricular arrhythmias.

Ranolazine Effectively Suppresses Atrial Fibrillation in the Setting of Heart Failure

“…Interestingly, whereas slowly dissociating I Na blockers such as propafenone induce significant PRR in both atria and ventricles, 20,21 rapidly dissociating I Na blockers like ranolazine and amiodarone are atrial-selective in their ability to induce PRR. 4,22 …”

“…Propafenone and flecainide are not atrial-selective in their action to block sodium channel activity. 3,21 The anti-AF efficacy of ranolazine in HF patients is poorly studied, but available evidence indicate that this drug can be an effective anti-AF agent in patients with HF. 25,26 Although the clinical antifibrillatory effect of long-term ranolazine therapy in patients has not been tested, our data suggest that ranolazine may be a better alternative to amiodarone or dofetilide in patients with HF, when taking into account both safety and anti-AF efficacy.…”

Atrial Remodeling in Permanent Atrial Fibrillation: Mechanisms and Pharmacological Implications

“…Due to more depolarized membrane potential during diastole, unlike in ventricles, fewer Na + channel will recover faster from inactivation in the atria; consequently I Na blockers known to bind more preferentially to the inactivated channel state will exhibit larger Na + channel blockade in the atria as compared to the ventricles [84]. Ranolazine ( Figure 3) was initially developed as an antianginal drug, but was soon recognized also to successfully suppressing ventricular EADs and to reduce transmural dispersion of APD [85]. In vitro electrophysiological investigations revealed that ranolazine blocks primarily late I Na but several other currents as I Kr , I Ks , and even possibly L-type calcium current (I CaL ) [86].. Ranolazine was shown to shown to reduce ischemic intracellular sodium and calcium overload, and to effectively suppress triggered activity, such as EADs.…”

Antiarrhythmic properties of novel antianginal drugs in dog and human cardiac preparations

“…mexiletine). In previous studies the drug was reported to produce atrial-predominant sodium channel block and postrepolarization refractoriness which was postulated in the mechanism of suppressing atrial fibrillation [29,31,32,36,38]. The investigators did not apply properly wide range of stimulation frequencies (BCL= 300-5000 ms) in the presence of ranolazine at therapeutically meaningful concentration using the conventional microelectrode technique.…”

“…In addition, ranolazine has been proposed to possess antiarrhythmic potential [26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45] which was principally related to the inhibition of sodium current (I Na ), rapid delayed rectifier potassium current (I Kr ) and calcium current (I Ca ) [27,[46][47][48][49][50]. A suppression of ventricular tachycardias by ranolazine after non-ST-segment elevation myocardial infarction has been proven in the MERLIN-TIMI 36 trial [51].…”