Effect in vitro of cyclic nucleotides-elevating agents on nitric oxide production by human granulocytes from type...

The present study was designed to investigate the hypothesis that cells from ill patients and from healthy subjects may have different reactivities under metabolic stimulation.

The study was performed with granulocytes from non-diabetic subjects and from type II -Non Insulin Dependent Diabetes mellitus (NIDDM) patients. The nitric oxide (NO) generation was comparatively determined by the nitrite concentration (micromolar of nitrite) after cell incubation in the presence of cyclic nucleotide-elevating agents.

Our results showed an inverse reactivity for granulocytes from diabetic patients when compared to non-diabetic subjects. Granulocytes were incubated in the presence of drugs that elevate the intracellular level of cyclic AMP aminophylline (AMF), dibutyryl cyclic AMP (dbcAMP)], cyclic GMP [8.Br. cyclic GMP(8.Br.cGMP) or levamisole (LEV)]. The cyclic AMP-elevating agents (AMF and d bcAMP) inhibited NO production by granulocytes from non-diabetic subjects and activated cells from diabetic patients. By contrast, cyclic GMP-elevating agents (8.Br.cGMP and LEV) activated cells from non-diabetic subjects and inhibited granulocytes from diabetic patients. The activation of NO generation by cyclic nucleotides was blocked by pretreatment of granulocytes with L-NAME.

The authors describe for the first time that both cyclic AMP and cyclic GMP were able to modulate nitric oxide production in human granulocytes and that cell reactivity in ill patients (diabetic) showed altered and inverse response in comparison to granulocytes from healthy subjects. This inverse reactivity possibly reflects a disease-induced adapted metabolic response. The consequences of this altered metabolic response on host defense and inflammation may be speculated, but further experiments are needed to confirm this hypothesis.