Flecainide sensitizes conduction to hyponatremia through an ephaptic mechanism.

Abstract

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, Iblocker E4031, or Iinhibitor 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 Kcurrents attenuated CV-[Na] sensitivity. CONCLUSION: SC LoF sensitizes conduction to changes in Nathrough ephaptic coupling and outward Kcurrent-mediated mechanisms. This study has implications for the management of plasma Nalevels in patients on SC-blocking drugs.