Nitric oxide-releasing oxatriazole derivatives inhibit human lymphocyte proliferation by a cyclic GMP-independent mechanism.

Two novel nitric oxide (NO)-releasing oxatriazole derivatives, GEA 3162 and GEA 3175, and an earlier known NO donor, S-nitroso-N-acetylpenicillamine (SNAP), inhibited cell proliferation and enhanced cGMP production in a concentration-dependent manner in human lymphocytes activated by lectin mitogen concanavalin A (ConA). The possible mediator role of cGMP in the antiproliferative action of NO donors was tested by pharmacological means. An inhibitor of guanylate cyclase, 1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one, inhibited NO donor-induced cGMP production, whereas the antiproliferative action of NO donors remained unaltered. Phosphodiesterase inhibitors zaprinast and 3-isobutyl-1-methylxanthine potentiated and prolonged NO donor-induced increase in the concentrations of cGMP but did not enhance the antiproliferative action of NO donors. In addition, two analogs of cGMP, 8-bromo-cGMP and a more cell-permeable compound, 8-p-chlorophenylthio-cGMP, did not inhibit ConA-stimulated lymphocyte proliferation when used in concentrations of up to 300 microM. At millimolar concentrations, 8-bromo-cGMP had a moderate inhibitory action. These results suggest that nitric oxide-releasing oxatriazole derivatives inhibit proliferative responses in human lymphocytes by a cGMP-independent manner.