Flecainide sensitizes conduction to hyponatremia through an ephaptic mechanism.

BACKGROUND

Studies suggest that voltage-gated sodium channel (SC) loss-of-function (LoF), often through the use of SC blockers, such as tricyclic anti-depressants, some recreational drugs, and importantly, class 1c anti-arrhythmics, sensitizes cardiac conduction to hyponatremia. However, the mechanism driving conduction velocity (CV) sensitivity to sodium ion (Na+) concentration ([Na+]) is unknown. We recently demonstrated CV-[Na+] sensitivity in haploinsufficient Scn5a+/- mouse and reduced CV-[Na+] sensitivity when ephaptic coupling (extracellular conduction by electric fields) is also reduced.

OBJECTIVE

We aimed to determine which mechanisms influence CV sensitivity to [Na+] during voltage-gated SC LoF induced by the class 1c anti-arrhythmic, flecainide.

METHODS

CV was measured by optical mapping of Langendorff-perfused guinea pig hearts with either 145 or 120 mM [Na+] under control conditions, with flecainide alone, and the combination of flecainide with ephaptic coupling uncouplers mannitol or peptide sequence Leu-Gln-Leu-Glu-Glu-Asp, Na+-calcium ion exchanger inhibitor SEA0400, Na+-potassium ion (K+) adenosine triphosphatase inhibitor ouabain, IKr blocker E4031, or IK1 inhibitor barium chloride. CV-[Na+] sensitivity was quantified as percent CV slowing in response to lowering Na+.

RESULTS

Reducing [Na+] under control conditions did not slow CV. Reducing [Na+] in the presence of flecainide significantly slowed conduction (ie, [Na+] sensitivity). Both ephaptic coupling uncouplers significantly attenuated CV-[Na+] sensitivity. Inhibiting the Na+-calcium ion exchanger did not significantly change CV-[Na+] sensitivity. However, inhibiting outward K+ currents attenuated CV-[Na+] sensitivity.

CONCLUSION

SC LoF sensitizes conduction to changes in Na+ through ephaptic coupling and outward K+ current-mediated mechanisms. This study has implications for the management of plasma Na+ levels in patients on SC-blocking drugs.