Vol. 286, Issue 1, 215-220, July 1998

Nitric Oxide-Releasing Oxatriazole Derivatives Inhibit Human Lymphocyte Proliferation by a Cyclic GMP-Independent Mechanism¹

Outi Kosonen , Hannu Kankaanranta , Mari Lähde, Pauli Vuorinen , Pauli Ylitalo and Eeva Moilanen

University of Tampere, Medical School, Department of Pharmacological Sciences, Tampere, Finland (O.K., H.K., M.L., P.V., P.Y., E.M.); and Departments of Clinical Chemistry (O.K., P.Y., E.M.), Clinical Microbiology (P.V.) and Respiratory Medicine (H.K.), Tampere University Hospital, Tampere, Finland

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 µM. 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.