Tetrodotoxin: sodium channel specific anti-arrhythmic activity

Abstract

Many Class I anti-arrhythmic drugs not only block the cardiac sodium channel but also block the calcium and/or potassium channels. The hypothesis tested in this study was that sodium channel blockade without blockade of calcium or potassium channels produced anti-arrhythmic activity in the treatment of malignant ventricular arrhythmias. The arrhythmia model consists of ventricular fibrillation induced by critically timed single extrastimuli at twice diastolic pacing threshold following 15 minutes of ischaemic injury in a rabbit heart perfused in vitro. Preparations were randomly assigned to either tetrodotoxin (a selective sodium channel blocking toxin) or vehicle. Ventricular fibrillation occurred in all vehicle treated preparations in response to single extrastimuli following ischaemic injury. Treatment with tetrodotoxin at concentrations of 0.1 to 1.0 micromolar protected some hearts from fibrillation, while at concentrations above 3 micromolar ventricular fibrillation was not inducible. Tetrodotoxin produced concentration dependent increases in ventricular effective refractory period and conduction time in the infarct zone which were associated with anti-arrhythmic activity. No concentration dependent change in action potential duration was seen with tetrodotoxin. Thus the electrophysiological and anti-arrhythmic activities of tetrodotoxin in this model demonstrate that the property of selective sodium channel blockade is sufficient to produce anti-arrhythmic activity.

Effect of Cardioactive Drugs on Action Potential Generation and Propagation in Embryonic Stem Cell-Derived Cardiomyocytes

“…The sodium inward current (I Na ) is the main current underlying the fast impulse propagation in the heart. It was shown that application of TTX results in prolongation of cardiac conduction time [28,29]. Applying TTX, we observed intermittent AP propagation blocks in a complex cardiac cluster containing narrow tissue strands.…”

Decrease in density of INa is in the common final pathway to heart block in murine hearts overexpressing calcineurin

“…Moreover, 300 -1,000 nM concentrations of encainide selectively block the cardiac sodium channel, with minimal effect on other cardiac currents (7,8). Encainide does inhibit the delayed rectifier current (I Kr) but only at high (micromolar) concentrations (12). In addition, we previously reported (11) that dofetilide, the selective I Kr channel blocker, never caused sudden death in this transgenic model.…”

“…In addition, we previously reported (11) that dofetilide, the selective I Kr channel blocker, never caused sudden death in this transgenic model. Although the more specific sodium channel blocker TTX was used in vitro, it is not possible to use TTX in vivo, since TTX blocks the neuronal sodium channels at nanomolar concentrations but the cardiac sodium channels only at micromolar concentrations (12). Thus, if TTX had been given in vivo to mice, only neurological responses would have been seen.…”

The Role of Late INa and Antiarrhythmic Drugs in EAD Formation and Termination in Purkinje Fibers

“…Blockade of sodium channel can also suppress ectopic beats that may also play a role in the genesis of fibrillatory activity in the heart. Indeed, the selective sodium channel blocker tetrodotoxin (TTX) has been shown to prevent ventricular fibrillation (VF) in isolated rabbit hearts 6 …”

“…Indeed, the selective sodium channel blocker tetrodotoxin (TTX) has been shown to prevent ventricular fibrillation (VF) in isolated rabbit hearts. 6 Recent evidence has shown that sodium channel activity contributes not only to the action potential upstroke, but can also affect the action potential plateau (Phase 2) and repolarization (Phase 3). This sustained activity is thought to be a result of three separate mechanisms.…”