Cardiac voltage-dependent sodium channels (VDSC) are known to be tetrodotoxin (TTX)-resistant. However, recent immunochemical studies suggest the presence of TTX-sensitive neuronal-type VDSC in the heart. Scanning ion conductance microscopy (SICM) coupled to electrophysiology was used to obtain more direct functional evidence. TTX sensitivities of whole-cell sodium currents (I-Na) in control and detubulated cells were compared. Addition of 200 nM TTX decreased I-Na. of control cells by 20%, whereas detubulated cells were hardly effected. The remaining current peaked slightly earlier and inactivation decay was faster (as in neuronal VDSC) than in detubulated cells. Single-channel activity was first assayed at random on the plasmalemma, and after topography had been revealed by SICM, at patched T-tubules openings. In the latter case, a single-channel conductance of 11-12 pS was observed with a higher rate of success. This study provides independent evidence for neuronal VDSC in cardiomyocytes where they could rapidly and synchronously couple T-tubule and cell surface depolarizations. (c) 2005 Elsevier Inc. All rights reserved.