Figure 2. Late Na⁺ current is not increased in cardiomyocytes expressing IQ/AA Na_V1.5.

(A–D) Exemplar whole cell Na⁺ current traces of ventricular cardiomyocytes isolated from nontransgenic, pWT, IQ/AA, and F1759A mice. Experiments designed to assess late Na⁺ current using a 190 ms depolarization from a holding potential of –110 to –30 mV in the absence and presence of 500 μM ranolazine or 40 μM TTX; intracellular solution contained 5 mM Na⁺ and extracellular solution contained 100 mM Na⁺. Horizontal scale bars: 50 ms; vertical scale bars: 10 pA/pF. (E) Graph of fraction of late Na⁺ current normalized to peak Na⁺ current. Mean ± SEM, ****P < 0.0001 by Kruskal-Wallis test with Dunn’s multiple comparison test. n = 23, 25, 29, and 31 cardiomyocytes from left to right. (F) Multichannel record from pseudo-WT myocyte shows rapid Na⁺ channel activation and inactivation, followed by a rare opening in the late phase, following 50 ms of depolarization (gray shaded region). Inset shows lone Na_V1.5 opening to unitary current level (dashed line) in the late phase. Vertical scale bar: 10 pA; horizontal scale bar: 100 ms. (G) Normalized ensemble-average open probability relation computed from 50–80 stochastic records. Inset shows low levels of late P_O following 50 ms of depolarization. Vertical scale bar: 25% for normalized P_O (P_O[t]/P_O,peak). P_O(t), time-dependent open probability; P_O,peak denotes the peak open probability. (H and I) Multichannel recordings of Na⁺ channels from IQ/AA mice show minimal late current similar to pWT myocytes. Format as in F and G. (J and K) Appreciable late Na⁺–channel openings were detected for F1759A mutant. Format as in F and G. (L) Graph of P_O normalized to peak P_O. Mean ± SEM, **P < 0.001 by Kruskal-Wallis test, **P < 0.01 by Dunn’s multiple comparison test.