Search

Background Vernakalant inhibits several potassium currents and causes a rate- and voltage-dependent inhibition of the sodium current. Objective The aim of this study was to evaluate the antiarrhythmic mechanism of vernakalant in normal and electrically remodeled atria. Methods Fourteen goats were instrumented with electrodes on both atria. Drug effects on refractory period (ERP), conduction velocity (CV), and atrial fibrillation cycle length (AFCL) were determined in normal goats (control) and after 2 (2dAF) or 11 (11dAF) days of pacing-induced atrial fibrillation (AF) in awake goats. To evaluate the contribution of changes in conduction and ERP, the same experiments were performed with flecainide and AVE0118. In a subset of goats, monophasic action potentials were recorded during anesthesia. Results Vernakalant dose-dependently prolonged ERP and decreased CV in CTL experiments. Both effects were maintained after 2dAF and 11dAF. After 11dAF, conduction slowed down by 8.2 ± 1.5 cm/s and AFCL increased by 55 ± 3 ms, leading to AF termination in 5 out of 9 goats. Monophasic action potential measurements revealed that ERP prolongation was due to enhanced postrepolarization refractoriness. During pacing, vernakalant had comparable effects on CV as flecainide, while effect on ERP was comparable to AVE0118. During AF, all compounds had comparable effects on median AFCL and ERP despite differences in their effects on CV during pacing. Conclusion The antiarrhythmic effect of vernakalant in the goat, at clinically relevant plasma concentrations, is based on both conduction slowing and ERP prolongation due to postrepolarization refractoriness. These electrophysiological effects were not affected by long-term electrical remodeling of the atria. more...

Background Vernakalant (VER) is a relatively atrial-selective antiarrhythmic drug capable of blocking potassium and sodium currents in a frequency- and voltage-dependent manner. Ranolazine (RAN) is a sodium-channel blocker shown to exert antiarrhythmic effects in pulmonary vein (PV) sleeves. dl-Sotalol (SOT) is a β-blocker commonly used in the rhythm-control treatment of atrial fibrillation. This study evaluated the electrophysiological and antiarrhythmic effects of VER, RAN, and SOT in canine PV sleeve preparations in a blinded fashion. Methods Transmembrane action potentials were recorded from canine superfused PV sleeve preparations exposed to VER (n = 6), RAN (n = 6), and SOT (n = 6). Delayed afterdepolarizations were induced in the presence of isoproterenol and high-calcium concentrations by periods of rapid pacing. Results In PV sleeves, VER, RAN, and SOT (3–30 μM) produced small (10–15 ms) increases in action potential duration. The effective refractory period, diastolic threshold of excitation, and the shortest S 1 –S 1 cycle length permitting 1:1 activation were significantly increased by VER and RAN in a rate- and concentration-dependent manner. VER and RAN significantly reduced V max in a concentration- and rate-dependent manner. SOT did not significantly affect the effective refractory period, V max , diastolic threshold of excitation, or the shortest S 1 –S 1 cycle length permitting 1:1 activation. All 3 agents (3–30 μM) suppressed delayed afterdepolarization–mediated triggered activity induced by isoproterenol and high calcium. Conclusions In canine PV sleeves, the effects of VER and RAN were similar and largely characterized by concentration- and rate-dependent depression of sodium-channel–mediated parameters, which were largely unaffected by SOT. All 3 agents demonstrated an ability to effectively suppress delayed afterdepolarization–induced triggers of atrial arrhythmia. more...

s Atrial fibrillation (AF) affects millions of people worldwide, and as longevity increases, the burden becomes greater. Triggers of AF often arise from the pulmonary veins (PVs), and there has been much emphasis on treating this arrhythmia by ablating these triggers. The use of antiarrhythmic drugs to suppress AF has been disappointing in that recurrence rates are high and side effects are common. Yet the search for newer antiarrhythmic agents continues. None so far have targeted the PVs in patients. The current arsenal of anti-AF agents includes amiodarone, flecainide, propafenone, sotalol, dofetilide, ibutilide, and dronedarone, although some are given by infusion, others are more “pill-in-the-pocket,” and others used for sustaining sinus rhythm after cardioversion. For all approaches, overall long-term efficacy is still low. Vernakalant is an investigational drug in the United States but has been approved in Europe for the conversion of AF. It is a very complex compound that is capable of blocking many channels: IKur, Ito, IKr, IKACh, INa. 2 In clinical trials compared with placebo, vernakalant rapidly converts short-term AF (3–48 hours). Side effects include dysgeusia and hypotension. Ranolazine is an approved antianginal drug capable of blocking multiple channels—IKr, late INa, and peak and late ca—and shares many similarities with amiodarone. 7 In wedge reparations, ranolazine suppressed delayed afterdepolarizaions (DADs) and reduced transmural dispersion of repolarizaion induced by the IKr blocker d-sotalol. Using whole-cell atch-clamp techniques, in canine myocytes, ranolazine prouces a use-dependent block of atrial sodium channels, leading o the suppression of AF. Ranolazine also reduced dofetilideinduced torsades de pointes episodes. In the MERLIN trial, 6560 patients with acute coronary syndrome were randomized to ranolazine or placebo. There was a trend of fewer new onset of AF episodes with use of ranolazine. d-Sotalol is approved for maintenance of sinus rhythm in delaying time to AF recurrence. It is also indicated for more...