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 IC(50) 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.
Department of Anesthesiology, Akita City Hospital, Akita 010-0933, Japan.
Shigehiro
S
Shibata
Kyoichi
K
Ono
Toshihiko
T
Iijima
D000200:Action Potentials / Q000187:drug effects; D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D002839:Chromans / Q000494:pharmacology; D051668:Delayed Rectifier Potassium Channels; D006168:Guinea Pigs; D006221:Halothane / Q000494:pharmacology; D006352:Heart Ventricles / Q000166:cytology; D066298:In Vitro Techniques; D008738:Methyl Ethers / Q000494:pharmacology*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000502:physiology; D018408:Patch-Clamp Techniques; D010880:Piperidines / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D024642:Potassium Channels, Voltage-Gated / Q000037:antagonists & inhibitors* / Q000502:physiology; D011725:Pyridines / Q000494:pharmacology; D000077149:Sevoflurane; D013449:Sulfonamides / Q000494:pharmacology; D013997:Time Factors
D018685:Anesthetics, Inhalation; D002839:Chromans; D051668:Delayed Rectifier Potassium Channels; D008738:Methyl Ethers; D010880:Piperidines; D026902:Potassium Channel Blockers; D024642:Potassium Channels, Voltage-Gated; D011725:Pyridines; D013449:Sulfonamides; C059983:potassium channel protein I(sk); C063968:E 4031; C103474:6-cyano-4-(N-ethylsulfonyl-N-methylamino)-3-hydroxy-2,2-dimethylchromane; D000077149:Sevoflurane; D006221:Halothane