Ito blockade by rapid pacing at pacing cycle length (PCL) 1 s or by 4-aminopyridine (4-AP) suppresses H2O2-induced and hypokalemia-induced early afterdepolarizations (EADs) in rabbit ventricular myocytes. A, No EADs arose under control conditions at PCL 6, 1, or 6 s in the presence of 4-AP (2 mmol/L). B and C, After exposure to H2O2 (1 mmol/L; B) or hypokalemia (2.7 mmol/L; C), EADs (*) occurred at PCL 6 s (row 1), but were suppressed by rapid pacing at PCL 1 s (row 2) or by adding 4-AP (row 3). Superimposed action potentials under the 3 conditions are shown below.
Virtual Ito reconstitutes H2O2-induced (A) and hypokalemia-induced (B) early afterdepolarizations (EADs) blocked by 4-aminopyridine (4-AP). Row 1: Action potentials (APs) were elicited during pacing at 6 s under control conditions. Row 2: H2O2 (1 mmol/L) or hypokalemia (2.7 mmol/L) induced EADs (*) during slow pacing at 6 s. Row 3: Ito blockade with 4-AP (2 mmol/L) suppressed EADs. Row 4: Representative parameter combinations of a virtual Ito that caused EADs to reappear. Rows 5 to 6: Representative parameter combinations of a virtual Ito that shortened AP duration and suppressed EAD reappearance by increasing the pedestal or Ito conductance.
Effects of on reappearance of pacing-suppressed early afterdepolarizations (EADs). Row 1: EADs induced by hypokalemia (2.7 mmol/L) at pacing cycle length (PCL) 6 s (not shown) were suppressed by shortening PCL to 1 s. Rows 2 to 4: A virtual Ito with τinact=25 ms and no pedestal reconstituted EADs (*) at an intermediate Ito conductance (=0.05 nS/pF, row 3), whereas smaller (0.01 nS/pF, row 2) or larger conductances (0.15 nS/pF, row 4) caused action potential duration shortening.
Effects of τinact on reappearance of pacing-suppressed early afterdepolarizations (EADs). Row 1: EADs induced by H2O2 (1 mmol/L) at pacing cycle length (PCL) 6 s (not shown) were suppressed by shortening PCL to 1 s. Rows 2 to 4: A virtual Ito with =0.05 nS/pF and no pedestal did not reconstitute EADs (*) for τinact=20 ms (row 2), but did when τinact was prolonged to 80 (row 3) or 100 ms (row 4).
Effects of the pedestal component on the reappearance of pacing-suppressed early afterdepolarizations (EADs). Row 1: EADs induced by H2O2 (1 mmol/L) at pacing cycle length (PCL) 6 s (not shown) were suppressed by shortening PCL to 1 s. Rows 2 to 6: A virtual Ito with =0.025 nS/pF and τinact=80 ms reconstituted EADs (*) for pedestals ≤50% (rows 2–5), but not for a pedestal of 75% (row 6).
Virtual Ito parameter combinations causing pacing-suppressed H2O2-induced or hypokalemia-induced early afterdepolarizations (EADs) to reappear. Graphs show (, τinact) combinations that did (solid circles) or did not (open circles) cause EADs to reappear at pacing cycle length (PCL) 1 s, using the protocols shown in Figures 3 to 5, for the different ranges of Ito pedestal components as indicated in A to D. A, Dashed black line outlines the border of the experimental region in parameter space causing EADs to reappear, compared to the predictions from a computer model (gray shaded area), adapted from Zhao et al.3B–D, Solid colored regions outline the experimental region in parameter space causing EADs to reappear for pedestals ranging from 10% to 24% (B), 25% to 49% (C), and 50% to 75% (D), compared with the no-pedestal case (black line reproduced from A). B, The red box indicates the typical parameter values for human ventricular Ito1,f in normal and failing hearts (see Table 1). No EADs re-emerged with pedestals >75%.
