Atrial selectivity of antiarrhythmic drugs

Abstract

New antiarrhythmic drugs for treatment of atrial fibrillation should ideally be atrial selective in order to avoid pro-arrhythmic effects in the ventricles. Currently recognized atrial selective targets include atrial Nav1.5 channels, Kv1.5 channels and constitutively active Kir3.1/3.4 channels, each of which confers atrial selectivity by different mechanisms. Na(+) channel blockers with potential- and frequency-dependent action preferentially suppress atrial fibrillation because of the high excitation rate and less negative atrial resting potential, which promote drug binding in atria. Kv1.5 channels are truly atrial selective because they do not conduct repolarizing current IKur in ventricles. Constitutively active IK,ACh is predominantly observed in remodelled atria from patients in permanent atrial fibrillation (AF). A lot of effort has been invested to detect compounds which will selectively block Kir3.1/Kir3.4 in their remodelled constitutively active form. Novel drugs which have been and are being developed aim at atrial-selective targets. Vernakalant and ranolazine which mainly block atrial Na(+) channels are clinically effective. Newly designed selective IKur blockers and IK,ACh blockers are effective in animal models; however, clinical benefit in converting AF into sinus rhythm (SR) or reducing AF burden remains to be demonstrated. In conclusion, atrial-selective antiarrhythmic agents have a lot of potential, but a long way to go.

Figure 1. Typical action potentials recorded from canine left (A) and human right atrial tissue (B) before and after exposure to various antiarrhythmic drugs

A, in healthy canine coronary perfused left atria stimulated at a rate of 2 s⁻¹, vernakalant, ranolazine and the hERG channel blocker d,l-sotalol prolonged APD during late repolarization phases. Note that vernaklant elevated the plateau, ranolazine slightly shortened the plateau phase, and d,l-sotalol did not affect it at all. Reproduced from Burashnikov et al. (2012), with permission of the publisher. B, similar effects of ranolazine and dofetilide (as an alternative example of a selective hERG channel blocker) in isolated right atrial trabeculae from patients in SR (stimulation rate 1 s⁻¹), but no plateau elevation with vernakalant (unpublished observations).

Figure 2. Effects of various I_Kur blockers on plateau elevation and action potential duration in human right atrial trabeculae from patients in sinus rhythm (SR) and atrial fibrillation (AF)

Stimulation rate 1 s⁻¹, temperature 37°C. Note that all I_Kur blockers shorten action potential during the final phase of repolarization in SR preparations, whereas they prolong the action potential duration in AF preparations (unpublished observations). For experimental details see Christ et al. (2008), Ford et al. (2013) and Wettwer et al. (2013).

Figure 3. Effects of carbachol and tertiapin-Q (TQ) on human atrial action potentials and I_K,ACh

A and B, action potentials (stimulation rate 1 s⁻¹) recorded in trabeculae. C, action potentials recorded in an isolated cardiomyocytes from a SR patient. Note, that TQ (100 nmol l⁻¹) hardly reversed or prevented the APD shortening induced by carbachol in multicellular preparations, but fully reversed the carbachol effect in isolated cells (unpublished observations). D, inhibitory effect of tertiapin on actelcholine-activated current in atrial cardiomyocytes from patients in SR and AF. Inset; inward rectifier current (basal current) activated by ramp clamp steps was analysed at −100 mV. The carbachol (2 μmol l⁻¹) stimulated current increase (I_K,ACh) which was fully reversible upon washout, was suppressed after exposure to tertiapin in a concentration-dependent manner. Reproduced from Dobrev et al. (2005), with permission of the publisher.