Mechanisms underlying the QT interval-prolonging effects of sevoflurane and its interactions with other QT-prolonging drugs.
BACKGROUND
Sevoflurane prolongs ventricular repolarization in patients, but the mechanisms are not fully characterized. The effects of sevoflurane on many cloned human cardiac ion channels have not been studied, and the interactions between sevoflurane and other drugs that prolong cardiac repolarization have not been detailed.


METHODS
The effects of sevoflurane on action potentials and L-type Ca channels in guinea pig myocytes were examined. Sevoflurane's effects on cloned human cardiac K channels and the cloned human cardiac Na channel were studied. The consequences of combining sevoflurane and the class III antiarrhythmic drugs sotalol or dofetilide on action potential duration were also examined.


RESULTS
Sevoflurane produced an increase in action potential duration at concentrations of 0.3-1 mm. Contrary to most drugs that delay ventricular repolarization, sevoflurane was without effect on the human ether-a-go-go-related gene cardiac potassium channel but instead produced a reduction in KvLQT1/minK K channel currents and inhibited the Kv4.3 K channel by speeding its apparent rate of inactivation. Sevoflurane had little effect on Na and Ca channel currents at concentrations of 1 mm or less. When the authors coadministered sevoflurane with sotalol or dofetilide, synergistic effects on repolarization were observed, resulting in large increases in action potential duration (up to 66%).


CONCLUSIONS
Prolonged ventricular repolarization observed with administration of sevoflurane results from inhibition of KvLQT1/minK and Kv4.3 cardiac K channels. Combining sevoflurane with class III antiarrhythmic drugs results in supra-additive effects on action potential duration. The results indicate that sevoflurane, when administered with this class of drug, could result in excessive delays in ventricular repolarization. The results suggest the need for further clinical studies.
Kang
Jiesheng
J
Department of Drug Safety Evaluation, Sanofi-Aventis U.S. Inc., Bridgewater, New Jersey 08807-0800, USA.
Reynolds
William P
WP
Chen
Xiao-Liang
XL
Ji
Junzhi
J
Wang
Hongge
H
Rampe
David E
DE
D000200:Action Potentials / Q000187:drug effects; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D016466:CHO Cells; D002469:Cell Separation; D006224:Cricetinae; D004347:Drug Interactions; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D007473:Ion Channels / Q000187:drug effects; D008133:Long QT Syndrome / Q000139:chemically induced* / Q000503:physiopathology; D008738:Methyl Ethers / Q000494:pharmacology*; D032383:Myocytes, Cardiac / Q000187:drug effects; D018408:Patch-Clamp Techniques; D010627:Phenethylamines / Q000494:pharmacology; D000077149:Sevoflurane; D013015:Sotalol / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology
D000319:Adrenergic beta-Antagonists; D018685:Anesthetics, Inhalation; D000889:Anti-Arrhythmia Agents; D007473:Ion Channels; D008738:Methyl Ethers; D010627:Phenethylamines; D013449:Sulfonamides; D000077149:Sevoflurane; D013015:Sotalol; C063533:dofetilide