Effects of some 1,4-dihydropyridine Ca antagonists on the blast transformation of rat spleen lymphocytes

Ca antagonists of different classes (verapamil, nifedipine, nicardipine, di ltiazem) in a concentration of 10(-5) M and higher are known to suppress Ca 2+ transport into the lymphocyte cytosol? changing a normal response of lym phocytes to mitogens and antigens and so inhibiting their proliferation, as well as IL-2-induced cell proliferation, and their receptor expression on the surface of lymphocytes without cell cytotoxicity. In the present work w e studied the effect of some 1,4-dihydropyridines (DHP) such as nimodipine, nicardipine, nifedipine, niludipine, cerebrocrast, etaftoron, as well as m etabolites of cerebrocrast: compounds 7 and 8, (four of the last were synth esized in the Latvian Institute of Organic Synthesis) on rat spleen isolate d lymphocyte activation and proliferation in vitro following stimulation wi th the mitogens concanavalin A (Con A) and recombinant interleukin-2 (IL-2) , insulin and insulin antibodies. Based on the experimental results we conc lude that in low concentrations (10(-7) to 10(-9) M) the tested 1,4-DHP Ca antagonists stimulated the process of rat spleen lymphocyte proliferation a nd DNA synthesis, especially cerebrocrast. It is proposed that these Ca ant agonists, as well as causing a concentration decrease of Ca2+, also activat ed phosphodiesterase, which in its turn, suppressed cAMP accumulation in th e lymphocytes and eventually increased Ca2+ ion transport in the cells. Cer ebrocrast among all the studied DHP Ca antagonists was the most potent in s tudies of activation of the lymphocytes in the presence of Con A, IL-2 and insulin, which indicates the number of suppressor and helper lymphocytes an d formation of insulin and interleukin receptors on their membrane surface. The increase in the lymphocyte suppressive activity produced by this compo und effect can prevent diabetes mellitus types I and II at the stages of pr e-diabetes, early and distant diabetes, from hyperexpression of insulin and its receptor antibodies. Copyright (C) 1999 John Wiley & Sons, Ltd.