Effects of halothane and isoflurane on fast and slow inactivation of humanheart hH1a sodium channels

Background: Cloning and heterologous expression of ion channels allow bioph ysical and molecular studies of the mechanisms of volatile anesthetic inter actions with human heart sodium channels. Volatile anesthetics may influenc e the development of arrhythmias arising from cardiac sodium channel dysfun ction. For that reason, understanding the mechanisms of interactions betwee n these anesthetics and cardiac sodium channels is important. This study ev aluated the mechanisms of volatile anesthetic actions on the cloned human c ardiac sodium channel (hH1a) alpha subunit. Methods: Inward sodium currents were recorded from human embryonic kidney ( HEK293) cells stably expressing hH1a channels. The effects of halothane and isoflurane on current and channel properties were evaluated using the whol e cell voltage-clamp technique. Results: Halothane at 0.47 and 1.1 mM and isoflurane at 0.54 and 1.13 raw s uppressed the sodium current in a dose- and voltage-dependent manner. Stead y state activation was not affected, but current decay was accelerated. The voltage dependence of steady state fast and slow inactivations was shifted toward more hyperpolarized potentials. The slope factor of slow but not fa st inactivation curves was reduced significantly. Halothane increased the t ime constant of recovery from fast inactivation. The recovery from slow ina ctivation was not affected significantly by either anesthetic. Conclusions: In a heterologous expression system, halothane and isoflurane interact with the hH1a channels and suppress the sodium current. The mechan isms involve acceleration of the transition from the open to the inactivate d state, stabilization of the fast and slow inactivated states, and prolong ation of the inactivated state by delayed recovery from the fast inactivate d to the resting state.