Sevoflurane Inhibition of the Slowly Activating Delayed Rectifier K⁺ Current in Guinea Pig Ventricular Cells

Abstract

Single ventricular cells were enzymatically isolated from guinea pig hearts and the effects of sevoflurane on the delayed rectifier K⁺ current were investigated by the patch clamp method. The rapidly (I_Kr) and slowly activating delayed rectifier K⁺ current (I_Ks) were isolated using chromanol 293B, a selective blocker for I_Ks or E4031 (N-[4-[[1-[2-(6-methyl-2-pyridinyl)ethyl]-4-piperidinyl]carbonyl]phenyl]methanesulfonamide dihydrochloride), a blocker for I_Kr. Sevoflurane and halothane decreased I_Ks in a concentration-dependent manner with an IC₅₀ value of 0.38 mM for sevoflurane and 1.05 mM for halothane. I_Ks inhibition was characterized by suppression of maximum conductance with little effect on activation kinetics. Inhibition occurred immediately after anesthetic application and recovered upon wash-out. In contrast to the marked inhibition of I_Ks, I_Kr was hardly affected by sevoflurane. Under the current clamp, sevoflurane prolonged the action potential duration in a reversible manner and this effect was more marked when I_Kr was inhibited by E4031. The results suggest that sevoflurane inhibits I_Ks, and not I_Kr, in a concentration-dependent manner at clinically relevant concentrations. The resulting prolongation of ventricular repolarization may partly account for the clinical observation of excessive QT prolongation by these anesthetics.