Differential modulation of the cardiac L- and T-type calcium channel currents by isoflurane

Abstract

Background: Volatile anesthetics exert their negative chronotropic and inotropic effects, in part by depressing the L- and T-type calcium channels. This study examines and compares the dose-dependent effects of isoflurane on atrial L- and T-type calcium currents (ICa,L and ICa,T) and ventricular ICa,L. Methods: Whole cell ICa was recorded from enzymatically isolated guinea pig cardiomyocytes. Current-voltage relations for atrial and ventricular ICa,L was obtained from holding potentials of -90 and -50 mV to test a potential of +60 mV in 10-mV increments. Atrial ICa,T was determined by subtraction of currents obtained from holding potentials of -50 and -90 mV. Steady state inactivation was determined using standard two-pulse protocols, and data were fitted with the Boltzmann equation. Results: Isoflurane depressed ICa in a dose-dependent manner, with Kd values of 0.23 ± 0.03, 0.34 ± 0.03, and 0.71 ± 0.02 mm of anesthetic for atrial ICa,T and ICa,L and ventricular ICa,L, respectively, and caused a significant (P < 0.05) hyperpolarizing shift in steady state inactivation. At 1.2 and 1.6 mm, isoflurane caused a significant (P < 0.05) depolarizing shift in the steady state activation in ventricular ICa,L but not in atrial ICa,L or ICa,T. In addition to the depression of ICa,L, isoflurane also induced a hyperpolarizing shift in the reversal potential of ICa for both atrial and ventricular L-type calcium channels. Conclusion: The results show that atrial ICa,T is more sensitive to isoflurane than atrial ICa,L, and ventricular ICa,L was the least responsive to the anesthetic. These differential sensitivities of the calcium channels in the atrial and ventricular chambers might reflect phenotypic differences in the calcium channels or differences in modulation by the anesthetic.