The cytoskeleton of the cardiomyocyte has been shown to modulate ion channel function. Cytoskeletal disruption in vitro alters Na ϩ channel kinetics, producing a late Na ϩ current that can prolong repolarization. This study describes the properties of the cardiac Na ϩ channel and cardiac repolarization in neonatal mice lacking ankyrin B , a cytoskeletal "adaptor" protein. Using whole-cell voltage clamp techniques, I Na density was lower in ankyrin B (Ϫ/Ϫ) ventricular myocytes than in wild-type

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... WT) myocytes (Ϫ307Ϯ26 versus Ϫ444Ϯ39 pA/pF, PϽ0.01). Ankyrin B (Ϫ/Ϫ) myocytes exhibited a hyperpolarizing shift in activation and inactivation kinetics compared with WT. Slower recovery from inactivation contributed to the negative shift in steady-state inactivation in ankyrin B (Ϫ/Ϫ). Single Na ϩ channel mean open time was longer in ankyrin B (Ϫ/Ϫ) versus WT at test potentials (V t ) of Ϫ40 mV (1.0Ϯ0.1 versus 0.61Ϯ0.04 ms, PϽ0.05) and Ϫ50 mV (0.8Ϯ0.1 versus 0.39Ϯ0.05 ms, PϽ0.05). Ankyrin B (Ϫ/Ϫ) exhibited late single-channel openings at V t Ϫ40 and Ϫ50 mV, which were not seen in WT. Late I Na contributed to longer action potential durations measured at 90% repolarization (APD 90 ) at 1 Hz stimulation in ankyrin B (Ϫ/Ϫ) compared with WT (354Ϯ26 versus 274Ϯ22 ms, PϽ0.05). From ECG recordings of neonatal mice, heart rates were slower in ankyrin B (Ϫ/Ϫ) than in WT (380Ϯ14 versus 434Ϯ13 bpm, PϽ0.01). Although the QT interval was similar in ankyrin B (Ϫ/Ϫ) and WT at physiological heart rates, QT-interval prolongation in response to heart rate deceleration was greater in ankyrin B (Ϫ/Ϫ). In conclusion, Na ϩ channels in ankyrin B (Ϫ/Ϫ) display reduced I Na density and abnormal kinetics at the whole-cell and single-channel level that contribute to prolonged APD 90 and abnormal QT-rate adaptation. (Circ Res. 2000;86:441-447.)