Fig. 2

Effects of crizotinib on ECG parameters in isolated mouse hearts. a Isolated mouse hearts were exposed to increasing concentrations of crizotinib as shown (0 – 5 μmol/L, n = 6-11 for each concentration) and HR was measured by ECG. A significant reduction in HR was observed with increasing concentrations of crizotinib (*, compared with preceding concentration, p < 0.001). b-d Isolated mouse hearts were exposed to increasing concentrations of crizotinib (0–5 μmol/L, n = 6-11 for each concentration), and the following ECG parameters were measured as described in Methods: PR interval (b) QRS interval (c) and QT interval (d). e Dose–response curve showing effect of crizotinib on HR (expressed as % of unstimulated control) over a range of crizotinib concentrations (0–10 μmol/L, n = 6-11 for each concentration). The half maximal inhibitory concentration (IC50) of crizotinib on HR was observed to be 1.7 ± 0.4 μmol/L. f HR was measured by ECG in isolated mouse hearts under basal conditions (control, white bar) and following exposure to crizotinib (1 μmol/L, light grey bar, n = 11), ivabradine (3 μmol/L, dark grey bar, n = 5), or ivabradine plus crizotinib (3 μmol/L and 1 μmol/L respectively, black bar, n = 5). A significant reduction in HR was observed with either crizotinib or ivabradine (*, compared with CTL, p < 0.001) and with ivabradine plus crizotinib compared with ivabradine alone (#, compared with ivabradine alone, p < 0.001)