Drugs that exhibit use-dependent Na channel blockade, including antiarrhythmic agents, tricyclic antidepressants, opiate-like analgesics, and cocaine, are linked with an increased susceptibility to cardiac arrhythmias and sudden death. Computer simulations indicate that Na channel blockade retards recovery of excitability, thereby increasing the spatial dispersion of refractoriness, a precursor of many cardiac arrhythmias. In isolated rabbit left atria, stimuli timed to occur at increasing intervals following conditioning stimuli reveal an unstable interval (vulnerable period) during which single stimuli initiate trains of responses. The vulnerable period is extended by use-dependent Na channel blockade and provides a model for assaying proarrhythmic potential and probing cardiac instability.