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 OBJECTIVE: We aimed to determine which mechanisms influence CV sensitivity to [Na METHODS: CV was measured by optical mapping of Langendorff-perfused guinea pig hearts with either 145 or 120 mM [Na RESULTS: Reducing [Na CONCLUSION: SC LoF sensitizes conduction to changes in Na