Gradient of sodium current across the left ventricular wall of adult rat hearts

Abstract

1. Gradients of ion channels across the left ventricular (LV) wall have been well characterized and it has been shown that disruption of such gradients leads to altered rates of repolarization across the wall, which is associated with the generation of arrhythmias. 2. We have hypothesized that a transmural gradient of I(Na) is present and have directly measured this current in adult rat myocytes isolated from both the epicardial and endocardial layers of the left ventricle. Currents were also recorded in right ventricular (RV) myocytes for comparison. 3. Peak inward I(Na) currents, at -30 mV, were -49.7 +/- 2.5 pA pF(-1) (n = 22), -32.9 +/- 3.2 pA pF(-1) (n = 16) and -49.7 +/- 3.7 pA pF(-1) (n = 24) for RV, LV epicardial and LV endocardial myocytes, respectively. No differences in the voltage dependence of inactivation, the voltage dependence of steady-state inactivation, or reactivation were reported. 4. Our results demonstrate that a gradient of sodium current density is present across the LV wall of adult rat hearts.

Figure 1. Representative action potential waveforms and Ca²⁺-independent transient outward K⁺ current (I_to) traces in cardiac myocytes

Action potentials from RV, LV epicardial and LV endocardial myocytes were elicited as outlined in Methods and are shown in A, C and E, respectively. Representative I_to traces for RV (B), LV epicardial (D) and LV endocardial myocytes (F) were recorded at command potentials of −40, 0 and +40 mV. Currents were normalized for cell capacitance.

Figure 2. I_Na densities recorded from myocardial cell populations

Representative families of RV (A), LV endocardial (B) and LV epicardial (C) sodium currents were elicited using 50 ms rectangular voltage steps from a holding potential of −90 mV to command potentials ranging from −100 to +20 mV in 5 mV steps. D, current-voltage relationship of I_Na density recorded from LV epicardial (▪; n = 16), LV endocardial (□; n = 22) and RV (•; n = 24) myocytes. Values are all normalized to cell capacitance and expressed as means ±s.e.m.* Significantly different (P < 0.05) compared to endocardial myocytes at the same membrane potential.

Figure 3. Voltage dependence of inactivation kinetics for RV (•), LV epicardial (▪) and LV endocardial (□) myocytes

Tau values were calculated by fitting I_Na traces to a single exponential decay equation and are plotted against command potential. Data points represent the mean ±s.e.m. for n = 10 myocytes.

Figure 4. Voltage dependence of sodium current steady-state inactivation and recovery from fast inactivation

A, plot of steady-state inactivation of I_Na is recorded as voltage versus relative peak current from LV epicardial (▪; n = 7), LV endocardial (□; n = 10) and RV (•; n = 15) myocytes. Data were normalized to peak inward current and expressed as the mean ±s.e.m.B, reactivation data were recorded using a paired-pulse protocol and expressed as the P2/P1 ratio for LV epicardial (▪; n = 13), LV endocardial (□; n = 11) and RV (•; n = 12) myocytes (means ±s.e.m.).