Author:

Keywords:

Adult, Benzimidazoles, Calcium Channel Blockers, Cell Division, Concanavalin A, DNA, Dose-Response Relationship, Drug, Humans, L-Lactate Dehydrogenase, Leucine, Leukocytes, Mononuclear, Male, Mibefradil, Nifedipine, Protein Kinase C, Pyrimidine Nucleosides, Tetradecanoylphorbol Acetate, Tetrahydronaphthalenes, Thymidine, Uridine, Science & Technology, Life Sciences & Biomedicine, Pharmacology & Pharmacy, proliferation, mononuclear cells, nifedipine, mibefradil, calcium, ANTIGEN RECEPTOR, HUMAN LYMPHOCYTES, JUN, ACTIVATION, GROWTH, GENES, AP-1, FOS, TRANSCRIPTION, MEMBRANE, 1115 Pharmacology and Pharmaceutical Sciences, 3214 Pharmacology and pharmaceutical sciences

Abstract:

To evaluate the role of protein kinase C (PKC) and intracellular calcium and particularly Ca(2+)-uptake in the initiation of lymphocyte mitogenesis, the proliferation of human peripheral blood mononuclear cells (PBMC) was investigated during calcium entry blockade with nifedipine (an L-type calcium channel blocker) and mibefradil (an L- and T-type calcium channel blocker with a higher selectivity for T-type channels). The rate of [3H]-thymidine, [3H]-uridine and [3H]-leucine incorporation into control and concanavalin A-stimulated PBMC cultured for 3 days in the presence or absence of the calcium channel blockers nifedipine or mibefradil (1, 10 or 50 microM) is assayed. Nifedipine and mibefradil concentration-dependently reduced cell number and [3H]-thymidine incorporation or de novo DNA synthesis in control and concanavalin A-stimulated PBMC, as well as de novo RNA and protein synthesis. The proliferative response of nifedipine- or mibefradil-treated cells was restored by addition of phorbol-12-myristate-13-acetate (PMA), an exogenous PKC activator. Our data show that PBMC treated with the Ca2+ channel blockers nifedipine or mibefradil are still capable of proliferating in response to PMA. However, in PKC-depleted cells, the proliferative response of PBMC was suppressed.