Abnormal cardiac Na+ channel properties and QT heart rate adaptation in neonatal ankyrin, knockout mice

The cytoskeleton of the cardiomyocyte has been shown to modulate ion channe l function. Cytoskeletal disruption in vitro alters Na+ channel kinetics, p roducing a late Na+ current that can prolong repolarization. This study des cribes the properties of the cardiac Na+ channel and cardiac repolarization in neonatal mice lacking ankyrin,, a cytoskeletal "adaptor" protein. Using whole-cell voltage clamp techniques, I-Na density was lower in ankyrin(B)( -/-) ventricular myocytes than in wild-type (WT) myocytes (-307+/-26 versus -444+/-39 pA/pF, P<0.01). Ankyrin(B)(-/-) myocytes exhibited a hyperpolari zing shift in activation and inactivation kinetics compared with WT. Slower recovery from inactivation contributed to the negative shift in steady-sta te inactivation in ankyrin(B)(-/-). Single Nac channel mean open time was l onger in ankyrin(B)(-/-) versus WT at test potentials (V-t) of -40 mV (1.0/-0.1 versus 0.61+/-0.04 ms, P<0.05) and -50 mV (0.8+/-0.1 versus 0.39+/-0. 05 ms, P<0.05). Ankyrin(B)(-/-) exhibited late single-channel openings at V -t -40 and -50 mV, which were not seen in WT. Late I-Na contributed to long er action potential durations measured at 90% repolarization (APD(90)) at 1 Hz stimulation in ankyrin(B)(-/-) compared with WT (354+/-26 versus 274+/- 22 ms, P<0.05), From ECG recordings of neonatal mice, heart rates were slow er in ankyrin(B)(-/-) than in WT (380+/-14 versus 433+/-13 bpm, P<0.01). Al though the QT interval was similar in ankyrin(B)(-/-) and WT at physiologic al heart rates, QT-interval prolongation in response to heart rate decelera tion was greater in ankyrin(B)(-/-). In conclusion, Na+ channels in ankyrin (B)(-/-) display reduced I-Na density and abnormal kinetics at the whole-ce ll and single-channel level that contribute to prolonged APD(90) and abnorm al QT-rate adaptation.