Isoflurane and Sevoflurane Modulate Inactivation Kinetics of Ca²⁺ Currents in Single Bullfrog Atrial Myocytes

Background: To clarify the mechanism(s) of anesthetic depression of myocardial Ca²⁺ currents, the effects of isoflurane and sevoflurane on the inactivation kinetics of Ca²⁺ current in single bullfrog atrial myocytes were studied. Methods: Freshly isolated bullfrog atrial myocytes were obtained with an enzymatic dispersion procedure. Ca²⁺ currents were recorded with a whole-cell voltage-clamp technique. Results: Both isoflurane (1.25, 2.5, 5.0 vol%) and sevoflurane (2.5, 5.0 vol%) decreased the peak amplitude of Ca²⁺ current (I_Ca) with a minimal change in the time to peak and the reversal potential. The inactivation kinetics studies revealed that (1) isoflurane (2.5 vol%) and sevoflurane (5.0 vol%) markedly reduced the time constant of inactivation in I_Ca to 55% and 75% of control, respectively; (2) isoflurane (2.5 vol%) shifted the midpoint (V_1/2) of steady-state inactivation curve of I_Ca toward negative by 2.3 mV; and (3) isoflurane (2.5 vol%) delayed the reactivation time constant of I_Ca to 119% of control. The further computer-simulation study demonstrated that the observed decrease of time constant by isoflurane (1.25, 2.5 vol%) and sevoflurane (2.5 vol%) can explain the reduction in amplitude of I_Ca. Conclusions: The depression of I_Ca by lower concentration of isoflurane (1.25, 2.5 vol%) and sevoflurane (2.5 vol%) mainly is due to the decrease of time constant and, at higher concentration, isoflurane and sevoflurane may affect the other membrane components.