British Journal of Anaesthesia, 2004, Vol. 92, No. 1 93-101
© 2004 The Board of Management and Trustees of the British Journal of Anaesthesia
Laboratory Investigations |
Local anaesthetic sensitivities of cloned HERG channels from human heart: comparison with HERG/MiRP1 and HERG/MiRP1T8A
1 Department of Anaesthesiology, University Hospital Hamburg Eppendorf, Martinistr. 52, D-20251 Hamburg, Germany. 2 Institute of Neural Signal Transduction, Center for Molecular Neurobiology, University of Hamburg, Germany
*Corresponding author. E-mail: patrick.friederich@zmnh.uni-hamburg.de
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 MiRP1T8A 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 IC50 values of 20 (SEM 2) µM (n=29), 10 (1) µM (n=40) and 20 (2) µM (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 MiRP1T8A 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. MiRP1T8A does not seem to confer an increased risk of severe cardiac side-effects to carriers of this common polymorphism.
Br J Anaesth 2004; 92: 93–101
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