Differential Inhibitory Actions of Multitargeted Tyrosine Kinase Inhibitors on Different Ionic Current Types in Cardiomyocytes

Figures

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  Figure 1. (Top) Effects of lapatinib (LAP) on QTc prolongation in the mouse model. (A) The changes of QTc prolongation among the sham mice and mice treated with LAP 40 mg/kg/day (LAP 40) and 100mg/kg/day (LAP 100). (B) The measurements of the heart rate in mice treated with LAP. * p < 0.05 by contrasts from one-way analysis of variance (ANOVA). The x-axis in the upper section is given at a standard scale in ECGs.

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  Figure 2. Effect of lapatinib (LAP) or sorafenib (SOR) on the slowly activating delayed-rectifier K+ current (IK(S)) recorded from H9c2 cells. (A) Representative IK(S) traces elicited by a depolarizing pulse from −50 to −10 mV (indicated in the upper part of (A)). Label ‘a’ is the control and labels ‘b’ and ‘c’ were obtained 2 min after the addition of 1 and 3 μM LAP, respectively. Arrowhead indicates the zero current level. In (B) and (C), labels ‘a’ and ‘b’ indicate the absence and presence of 3 μM LAP, respectively. The current trajectories shown in (B) were satisfactorily fitted by a single exponential (indicated by the smooth line) with an activation time constant (τact) value of 74.8 msec (a, in the control) and 126.5 msec (b, in the presence of LAP). Those in (C) were fitted by a two-exponential process with the slow and fast deactivation time constant (τdeact) values of 90.3 and 35.3 msec (a, in the control) and 60.7 and 31.5 msec (b, in the presence of LAP). (D) Concentration-dependent inhibition of IK(S) by LAP or SOR (n = 8–11 for each point). The relations between the normalized amplitude of IK(S) and the concentration of LAP or SOR are illustrated. The values of IC50 in the…

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  Figure 3. Effect of LAP on erg-mediated K+ current (IK(erg)) in H9c2 cells. (A) Superimposed current traces obtained when the cell was 1-sec hyperpolarized from −10 mV to various potentials, as indicated in the uppermost part. Current traces labeled ‘a’ are the controls and those labeled ‘b’ were obtained in the presence of 10 μM LAP. The different colors depicted in current traces of ‘a’ and ‘b’ correspond to those in the voltage protocol applied (the uppermost part). (B) Averaged I–V relationships for the peak amplitude of deactivating IK(erg) in the absence (□) and presence (■) of 10 μM LAP (n = 9–10 for each point). Current amplitudes were measured at the beginning of each hyperpolarizing pulse.

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  Figure 4. Inhibitory effect of SOR on inwardly-rectifying K+ current (IK(IR)) in neonatal rat ventricular myocytes (NRVMs). (A) Superimposed IK(IR) traces obtained during the control (a) and in the presence of 3 μM SOR (b) and 10 μM SOR (c). Inset indicates the ramp voltage protocol used. (B) Bar graph showing the effect of SOR (3 and 10 μM) on the IK(IR) amplitude measured at the level of −150 mV (n = 9). * Significantly different from the control, p < 0.05 by contrasts from one-way analysis of variance (ANOVA).

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  Figure 5. Inhibitory effect of SOR on the voltage-gated Na+ current (INa) in NRVMs. (A) Superimposed INa traces when a cell was depolarized from −80 to −10 mV (indicated in the inset). Label ‘a’ is the control and label ‘b’ and ‘c’ were obtained 2 min after the application of 3 and 10 μM SOR, respectively. Arrowhead indicates the zero current level, and the calibration mark applies to all current traces. (B) Averaged I–V relationships of the peak INa obtained in the absence (●) and presence (○) of 10 μM SOR (n = 8–10 for each point). The current amplitudes were measured at the beginning of each depolarizing pulse. * Significantly different from controls (p < 0.05).

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  Figure 6. Effect of SOR on the membrane potential in cultured NRVMs. Current-clamp potential recordings were made and cells were bathed in normal Tyrode’s solution containing 1.8 mM CaCl2. Potential trace labeled ‘a’ is the control, and those labeled ‘b’ and ‘c’ were obtained during the exposure to 1 and 3 μM SOR, respectively.