Larger late sodium conductance in M cells contributes to electrical heterogeneity in canine ventricle

Abstract

Action potentials and whole cell sodium current were recorded in canine epicardial, midmyocardial, and endocardial myocytes in normal sodium at 37°C. Tetrodotoxin (TTX) reduced the action potential duration of midmyocardial cells to a greater degree than either epicardial or endocardial cells. Whole cell recordings in potassium-free and very-low-chloride solutions revealed a slowly decaying current that was completely inhibited by 5 μM TTX or replacement of external and internal sodium with the impermeant cation N-methyl-d-glucamine. Late sodium current density at 0 mV was 47% greater in midmyocardial cells and averaged −0.532 ± 0.058 pA/pF in endocardial, −0.463 ± 0.068 pA/pF in epicardial, and −0.785 ± 0.070 pA/pF in midmyocardial cells. Neither the frequency dependence of late sodium current nor its recovery from inactivation exhibited transmural differences. After a 4.5-s pulse to −30 mV, late sodium current recovered with a single time constant of 140 ms. We conclude that a larger late sodium conductance in midmyocardial cells will favor longer action potentials in these cells. More importantly, drugs that slow inactivation of sodium channels will produce a nonuniform response across the ventricular wall that is proarrhythmic.