Sevoflurane inhibition of the slowly activating delayed rectifier K+ current in guinea pig ventricular cells

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 l(Ks), and not I-Kr,I-, 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.