The goal was to terminate atrial fibrillation (AF) by targeting atrioventricular differences in ionic properties.

Optical mapping was used to record electrical activity during carbachol (0.25–0.5 μM)-induced AF in pig hearts. The atrial-specific current, I_Kur, was blocked with 100 μM 4-aminopyridine (4-AP) or with 0.5 μM DPO-1. Hearts in AF and ventricular fibrillation (VF) were also subjected to increasing levels of extracellular K⁺ ([K⁺]_o: 6–12 mM), compared with controls (4 mM). We hypothesized that due to the more negative steady-state half inactivation voltage for the atrial Na⁺ current, I_Na, compared with the ventricle, AF would terminate before VF in hyperkalaemia. Mathematical models were used to interpret experimental findings. The I_Kur block did not terminate AF in a majority of experiments (6/9 with 4-AP and 3/4 with DPO-1). AF terminated in mild hyperkalaemia ([K⁺]_o ≤ 10.0 mM; N = 8). In contrast, only two of five VF episodes terminated at the maximum ([K⁺]_o: 12 mM [K⁺]_o). The I_Kur block did not terminate a simulated rotor in cholinergic AF because its contribution to repolarization was dwarfed by the large magnitude of the acetylcholine-activated K⁺ current (I_K,ACh). Simulations showed that the lower availability of the atrial Na⁺ current at depolarized potentials, and a smaller atrial tissue size compared with the ventricle, could partly explain the earlier termination of AF compared with VF during hyperkalaemia.

I _Kur is an ineffective anti-arrhythmic drug target in cholinergic AF. Manipulating Na⁺ current ‘availability’ might represent a viable anti-arrhythmic strategy in AF.