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Enhanced effects of isoflurane on the long QT syndrome 1-associated A341V mutant. Anesthesiology 2015 Apr;122(4):806-20

Date

01/15/2015

Pubmed ID

25585005

Pubmed Central ID

PMC4366337

DOI

10.1097/ALN.0000000000000583

Scopus ID

2-s2.0-84937251640 (requires institutional sign-in at Scopus site)   8 Citations

Abstract

BACKGROUND: The impact of volatile anesthetics on patients with inherited long QT syndrome (LQTS) is not well understood. This is further complicated by the different genotypes underlying LQTS. No studies have reported on the direct effects of volatile anesthetics on specific LQTS-associated mutations. We investigated the effects of isoflurane on a common LQTS type 1 mutation, A341V, with an unusually severe phenotype.

METHODS: Whole cell potassium currents (IKs) were recorded from HEK293 and HL-1 cells transiently expressing/coexpressing wild-type KCNQ1 (α-subunit), mutant KCNQ1, wild-type KCNE1 (β-subunit), and fusion KCNQ1 + KCNE1. Current was monitored in the absence and presence of clinically relevant concentration of isoflurane (0.54 ± 0.05 mM, 1.14 vol %). Computer simulations determined the resulting impact on the cardiac action potential.

RESULTS: Isoflurane had significantly greater inhibitory effect on A341V + KCNE1 (62.2 ± 3.4%, n = 8) than on wild-type KCNQ1 + KCNE1 (40.7 ± 4.5%; n = 9) in transfected HEK293 cells. Under heterozygous conditions, isoflurane inhibited A341V + KCNQ1 + KCNE1 by 65.2 ± 3.0% (n = 13) and wild-type KCNQ1 + KCNE1 (2:1 ratio) by 32.0 ± 4.5% (n = 11). A341V exerted a dominant negative effect on IKs. Similar differential effects of isoflurane were also observed in experiments using the cardiac HL-1 cells. Mutations of the neighboring F340 residue significantly attenuated the effects of isoflurane, and fusion proteins revealed the modulatory effect of KCNE1. Action potential simulations revealed a stimulation frequency-dependent effect of A341V.

CONCLUSIONS: The LQTS-associated A341V mutation rendered the IKs channel more sensitive to the inhibitory effects of isoflurane compared to wild-type IKs in transfected cell lines; F340 is a key residue for anesthetic action.

Author List

Mikuni I, Torres CG, Bakshi T, Tampo A, Carlson BE, Bienengraeber MW, Kwok WM

Author

Wai-Meng Kwok PhD Professor in the Anesthesiology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Action Potentials
Anesthetics, Inhalation
HEK293 Cells
Humans
Isoflurane
Long QT Syndrome
Mutation