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Local anaesthetic sensitivities of cloned HERG channels from human heart: comparison with HERG/MiRP1 and HERG/MiRP1 T8A.

Abstract：

BACKGROUND:Myocardial potassium channels are complexes formed by different subunits. The subunit composition may influence the cardiotoxic action of local anaesthetics. The effects of amide local anaesthetics on HERG channels co-expressed with the putative subunit MiRP1 have not been established. It is also unclear if the common polymorphism MiRP1(T8A) that predisposes individuals to drug-induced cardiac arrhythmia increases local-anaesthetic sensitivity of HERG/MiRP1 channels. This may suggest the presence of genetic risk factors for local-anaesthetic-induced cardiac arrhythmia. METHODS:Whole-cell patch-clamp recordings and site-directed mutagenesis were combined to compare local anaesthetic sensitivities of cloned and mutated human potassium channel subunits. The ion channels were activated by a protocol that approximated ventricular action potentials. RESULTS:The amide local anaesthetics bupivacaine, levobupivacaine and ropivacaine inhibited HERG channels at toxicologically relevant concentrations, with IC(50) values of 20 (SEM 2) micro M (n=29), 10 (1) micro M (n=40) and 20 (2) micro M (n=49), respectively. Hill coefficients were close to unity. There were no indications of qualitative differences in channel inhibition between the three anaesthetics. The putative subunit MiRP1 did not alter local anaesthetic sensitivity of HERG channels. The common single nucleotide polymorphism producing MiRP1(T8A) did not increase local anaesthetic sensitivity of HERG/MiRP1 channels. CONCLUSIONS:Amide local anaesthetics target HERG and HERG/MiRP1 channels with identical potency. The effects on these ion currents may significantly contribute to local-anaesthetic-induced cardiac arrhythmia. MiRP1(T8A) does not seem to confer an increased risk of severe cardiac side-effects to carriers of this common polymorphism.

journal_name

Br J Anaesth

journal_title

British journal of anaesthesia

authors

Friederich P,Solth A,Schillemeit S,Isbrandt D

doi

10.1093/bja/aeh026

subject

Has Abstract

pub_date

2004-01-01 00:00:00

pages

93-101

issue

1

eissn

0007-0912

issn

1471-6771

pii

S0007-0912(17)36235-9

journal_volume

92

pub_type

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