COMPARISON OF EFFECT OF A PANEL OF MEMBRANE CHANNEL BLOCKERS ON THE PROLIFERATIVE, CYTOTOXIC AND CYTOADHERENCE ABILITIES OF HUMAN PERIPHERAL-BLOOD LYMPHOCYTES

The ability of human peripheral blood lymphocytes (PBMNC) to incorpora te tritiated thymidine upon stimulation with concanavalin A, to perfor m natural cytotoxic (NK) activity and to form two types of spontaneous ''rosettes'' with sheep red blood cells (SRBC) upon in vitro treatmen t with membrane channel blockers of different specificity was estimate d. All five channel blockers used, i.e., verapamil, nifedipine, diltia zem, saxitoxin and tetraethylammonium exerted a biphasic, dose-depende nt effect on the Con A-induced proliferation of PBMNC. Verapamil, saxi toxin and nifedipine significantly increased the percentage of PBMNC f orming spontaneously ''active'' rosettes with the SRBC. All channel mo difiers tested for this ability decreased the percentage of PBMNC form ing ''late'' rosettes. Natural killer activity was significantly decre ased in the presence of micromolar concentrations of calcium antagonis ts as well as when the cells were treated with tetraethylammonium. The results of all four parameters tested were also compared with these o btained in a group of patients treated with 300 mg per day verapamil f or two weeks preceding the tests. In this case we have found that trea tment in vivo significantly decreased the response of PBMNC to mitogen stimulation, but it was without effect on either NK cytotoxicity or r osette formation. Cells of verapamil-treated patients did not show inc reased response to Con A in the presence of low concentration of the b locker in vitro. Also, they were not able to form more ''active'' rose ttes when treated with 1-100 nM verapamil. We believe that apparent bi -directional pattern of action of calcium, sodium and potassium channe l blockers on the proliferation and rosette formation of human PBMNC c an be explained by two sets of events producing opposite results. Firs t, we suggest that at respectively low concentrations of the blockers all of them generate uniform modulation of transmembrane electrical po tential (depolarization) of lymphocytes, Depolarization promotes cell adhesion and is probably beneficial for early stages of the response t o mitogen. At higher concentrations, this effect is overshadowed by ot her pharmacological actions of the blockers, of mostly inhibitory char acter.