The ultrarapid delayed rectifier current (IK,ur) plays a significant role in human atrial repolarization and is generally believed to show little rate dependence because of slow and partial inactivation. This study was designed to evaluate in detail the properties and consequences of IK,ur inactivation in isolated human atrial myocytes. IK,ur inactivated with a biexponential time course and a half-inactivation voltage of -7.5 +/- 0.6 mV (mean +/- SE), with complete inactivation during 50-s pulses to voltages positive to +10 mV (37 degreesC). Recovery from inactivation proceeded slowly, with time constants of 0.42 +/- 0.06 and 7.9 +/- 0.9 s at -80 mV (37 degreesC). Substantial frequency dependence was observed at 37 degreesC over a clinically relevant range of frequencies. Inactivation was faster and occurred at more positive voltages at 37 degreesC compared with room temperature. The voltage and time dependencies of Kv1.5 inactivation were studied in Xenopus oocytes to avoid overlapping currents and strongly resembled those of IK,ur in native myocytes. We conclude that, while IK,ur inactivation is slow, it is extensive, and slow recovery from inactivation confers important frequency dependence with significant consequences for understanding the role of IK,ur in human atrial repolarization.