Effects of bretylium tosylate on voltage-gated potassium channels in human T lymphocytes.
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.
Gáspár
R
R
Department of Biophysics, University Medical School, Debrecen, Hungary.
Panyi
G
G
Ypey
D L
DL
Krasznai
Z
Z
Vereb
G
G
Pieri
C
C
Damjanovich
S
S
D001950:Bretylium Tosylate / Q000494:pharmacology*; D002462:Cell Membrane / Q000187:drug effects / Q000502:physiology; D004594:Electrophysiology; D006801:Humans; D066298:In Vitro Techniques; D015640:Ion Channel Gating / Q000187:drug effects*; D007700:Kinetics; D015221:Potassium Channels / Q000187:drug effects* / Q000502:physiology; D013601:T-Lymphocytes / Q000187:drug effects* / Q000502:physiology
D015221:Potassium Channels; D001950:Bretylium Tosylate