THE ANTIARRHYTHMIC AGENT BERTOSAMIL INDUCES INACTIVATION OF THE SUSTAINED OUTWARD K+ CURRENT IN HUMAN ATRIAL MYOCYTES

1 In whole-cell patch-clamped human atrial myocytes, the antiarrhythmi c agent bertosamil (10 mu M) inhibited the sustained component, I-sus (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 mu M) inhibited both I-t and I-sus. 2 Suppression of I-sus and stimulation of I-t by 10 mu M bertosamil was observed on renewed stimulation following a 2 m in rest period during which the drug was applied and persisted after w ashout, indicating a rest-dependent effect of bertosamil on the outwar d K+ current. 3 Cell dialysis with an internal solution containing 10 mu M bertosamil increased both I-t (78.0+/-14.7%) and I-total (26.7+/- 8.4%) and inhibited I-sus (28.9+/-6.3%, n=6). In the presence of intra cellular bertosamil, external application of the drug inhibited I-t an d I-sus in a concentration-dependent and use-dependent manner. 4 Follo wing the suppression of I-sus by 200 mu M 4-aminopyridine (4-AP), bert osamil (10 mu M) inhibited I-t. Washout of 4-AP was associated with a larger I-t amplitude than that observed in control conditions. In myoc ytes characterized by a prominent I-sus and lack of I-t, bertosamil (1 0 mu M) induced a rapid and partial inactivation of the current, toget her with inward rectification of the current measured at the end of th e test pulse. 5 In the presence of bertosamil the activation/voltage r elationships, 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 inactivat ion of sustained outward current which leads to an apparent increase i n I-t and decrease in I-sus. This effect, which was distinct from the use-dependent inhibition of the outward K+ current, could represent a new antiarrhythmic mechanism.