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, I(Kr) blocker E4031, or I(K1) 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.