The antiarrhythmic agent bertosamil induces inactivation of the sustained outward K+ current in human atrial myocytes

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Abstract
1. In whole-cell patch-clamped human atrial myocytes, the antiarrhythmic agent bertosamil (10 microM) inhibited the sustained component, Isus (38.6 +/- 3.1%), and enhanced the inactivating component, I(t) (9.1 +/- 6.1%), of the outward K+ current elicited by 750 ms test pulses from -60 mV to +50 mV. Higher concentrations of bertosamil (> 10 microM) inhibited both I(t) and Isus. 2. Suppression of Isus and stimulation of I(t) by 10 microM bertosamil was observed on renewed stimulation following a 2 min rest period during which the drug was applied and persisted after washout, indicating a rest-dependent effect of bertosamil on the outward K+ current. 3. Cell dialysis with an internal solution containing 10 microM bertosamil increased both I(t) (78.0 +/- 14.7%) and Itotal (26.7 +/- 8.4%) and inhibited Isus (28.9 +/- 6.3%, n = 6). In the presence of intracellular bertosamil, external application of the drug inhibited I(t) and Isus in a concentration-dependent and use-dependent manner. 4. Following the suppression of Isus by 200 microM 4-aminopyridine (4-AP), bertosamil (10 microM) inhibited I(t). Washout of 4-AP was associated with a larger I(t) amplitude than that observed in control conditions. In myocytes characterized by a prominent Isus and lack of I(t), bertosamil (10 microM) induced a rapid and partial inactivation of the current, together with inward rectification of the current measured at the end of the test pulse. 5. In the presence of bertosamil the activation/voltage relationships, steady-state inactivation and recovery from inactivation of I(t) were markedly modified, pointing to changes in the conductance underlying I(t). 6. We conclude that bertosamil induces rapid inactivation of sustained outward current which leads to an apparent increase in I(t) and decrease in Isus. This effect, which was distinct from the use-dependent inhibition of the outward K+ current, could represent a new antiarrhythmic mechanism.