Effects of halothane and isoflurane on fast and slow inactivation of human heart hH1a sodium channels.
BACKGROUND
Cloning and heterologous expression of ion channels allow biophysical and molecular studies of the mechanisms of volatile anesthetic interactions with human heart sodium channels. Volatile anesthetics may influence the development of arrhythmias arising from cardiac sodium channel dysfunction. For that reason, understanding the mechanisms of interactions between these anesthetics and cardiac sodium channels is important. This study evaluated the mechanisms of volatile anesthetic actions on the cloned human cardiac 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 whole cell voltage-clamp technique.


RESULTS
Halothane at 0.47 and 1.1 mM and isoflurane at 0.54 and 1.13 mM suppressed the sodium current in a dose- and voltage-dependent manner. Steady 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 fast inactivation curves was reduced significantly. Halothane increased the time constant of recovery from fast inactivation. The recovery from slow inactivation 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 mechanisms involve acceleration of the transition from the open to the inactivated state, stabilization of the fast and slow inactivated states, and prolongation of the inactivated state by delayed recovery from the fast inactivated to the resting state.
Stadnicka
A
A
Department of Anesthesiology, Medical College of Wisconsin, Milwaukee 53226, USA. astadnic@mcw.edu
Kwok
W M
WM
Hartmann
H A
HA
Bosnjak
Z J
ZJ
D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006221:Halothane / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects*; D006801:Humans; D007530:Isoflurane / Q000494:pharmacology*; D015222:Sodium Channels / Q000187:drug effects*
D018685:Anesthetics, Inhalation; D015222:Sodium Channels; D007530:Isoflurane; D006221:Halothane