Halothane inhibition of recombinant cardiac L-type Ca2+ channels expressed in HEK-293 cells

Kevin J. Gingrich, Son Tran, Igor M. Nikonorov, Thomas J. Blanck

Research output: Contribution to journalArticle

8 Scopus citations

Abstract

Background: Volatile anesthetics depress cardiac contractility, which involves inhibition of cardiac L-type calcium channels. To explore the role of voltage-dependent inactivation, the authors analyzed halothane effects on recombinant cardiac L-type calcium channels (α1Cβ 2a and α1Cβ2aα2/ δ1), which differ by the α21 subunit and consequently voltage-dependent inactivation. Methods: HEK-293 cells were transiently cotransfected with complementary DNAs encoding alc tagged with green fluorescent protein and β2a, with and without α21. Halothane effects on macroscopic barium currents were recorded using patch clamp methodology from cells expressing α1Cβ2a and α1Cβ2aα21 as identified by fluorescence microscopy. Results: Halothane inhibited peak current (Ipeak) and enhanced apparent inactivation (reported by end pulse current amplitude of 300-ms depolarizations [I300]) in a concentration-dependent manner in both channel types. α2/ δ1 coexpression shifted relations leftward as reported by the 50% inhibitory concentration of Ipeak and I300/I peak for α1Cβ2a (1.8 and 14.5 mM, respectively) and α1Cβ2aα2/ δ1 (0.74 and 1.36 mM, respectively). Halothane reduced transmembrane charge transfer primarily through Ipeak depression and not by enhancement of macroscopic inactivation for both channels. Conclusions: The results indicate that phenotypic features arising from α2/ δ1 coexpression play a key role in halothane inhibition of cardiac L-type calcium channels. These features included marked effects on Ipeak inhibition, which is the principal determinant of charge transfer reductions. Ipeak depression arises primarily from transitions to nonactivatable states at resting membrane potentials. The findings point to the importance of halothane interactions with states present at resting membrane potential and discount the role of inactivation apparent in current time courses in determining transmembrane charge transfer.

Original languageEnglish (US)
Pages (from-to)1156-1166
Number of pages11
JournalAnesthesiology
Volume103
Issue number6
DOIs
StatePublished - Dec 2005

ASJC Scopus subject areas

  • Anesthesiology and Pain Medicine

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