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 accel erated the inactivation and deactivation of the K+ current but did not influence the kinetics of activation or the voltage dependence of act ivation and steady state inactivation of the K+ conductance. The perce ntage of drug-induced block was independent of membrane potential. Kchannel block by bretylium tosylate was partially and slowly removable by washing with drug-free extracellular solution. Bovine serum albumi n (10 mg/ml) in the bath lifted the drug-induced block almost instanta neously, although not completely. In control experiments bovine serum albumin increased the inactivation time constant of the K+ channels bu t left the peak K+ current amplitude unaffected. On the basis of the e xperimental evidence, a gating-dependent allosteric interaction is sug gested for the mechanism of drug action. The effective dose range, tim e of exposure, and reversibility of bretylium tosylate-induced K+ chan nel block correlated well with the same parameters of the drug-induced inhibition of T lymphocyte activation. The reported effects of bretyl ium tosylate on T cell mitogenesis can be regarded partly as a consequ ence of its blocking effects on voltage-gated K+ channels.