Effects of bretylium tosylate on voltage-gated potassium channels in human T lymphocytes

Rezso Cáspár, György Panyi, Dirk L. Ypey, Zoltán Krasznai, György Vereb, Carlo Pieri, Sándor Damjanovich

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Abstract

Using the patch-clamp technique, we determined that bretylium tosylate, a quaternary ammonium compound possessing immunomodulating activity, decreased the whole-cell K+ current in human T lymphocytes, in a dose-dependent manner, in the 0.05-5 mM extracellular concentration range. Bretylium tosylate prolonged the recovery from inactivation and accelerated the inactivation and deactivation of the K+ current but did not influence the kinetics of activation or the voltage dependence of activation and steady state inactivation of the K+ conductance. The percentage of drug-induced block was independent of membrane potential K+ channel block by bretylium tosylate was partially and slowly removable by washing with drug-free extracellular solution. Bovine serum albumin (10 mg/ml) in the bath lifted the drug-induced block almost instantaneously, although not completely. In control experiments bovine serum albumin increased the inactivation time constant of the K+ channels but left the peak K+ current amplitude unaffected. On the basis of the experimental evidence, a gating-dependent allosteric interaction is suggested for the mechanism of drug action. The effective dose range, time of exposure, and reversibility of bretylium tosylate-induced K+ channel block correlated well with the same parameters of the drug-induced inhibition of T lymphocyte activation. The reported effects of bretylium tosylate on T cell mitogenesis can be regarded partly as a consequence of its blocking effects on voltage-gated K+ channels.

Original languageEnglish
Pages (from-to)762-766
Number of pages5
JournalMolecular pharmacology
Volume46
Issue number4
Publication statusPublished - Oct 1 1994

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ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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