Potentiation and inhibition of fMLP-activated exocytosis in neutrophils by exogenous nitric oxide

Exogenous nitric oxide (NO), not derived from NO-donors, but applied directly, could enhance exocytosis of rabbit peritoneal neutrophils induced by suboptimal concentrations of the chemotactic peptide fMLP. The enhancement was maximal at 30 mu M NO. Higher concentrations of NO strongly inhibited fMLP-induced exocytosis. The potentiation of fMLP-induced exocytosis by NO could not be reversed by the inhibitors of guanosine-3',5'-cyclic monophosphate (cGMP) accumulation, LY-83583 and methylene blue, or the antagonists of cGMP-dependent protein kinase, Rp-8-pCPT-cGMPS and Rp-8-Br-cGMPS. The concentration of NO needed to enhance fMLP-induced exocytosis was much higher than the concentration leading to an increase in intracellular cGMP levels. These observations suggest that the enhancement of exocytosis by NO is not likely to be mediated by cGMP. At the concentration which inhibited fMLP-induced exocytosis, NO reduced the intracellular level of glutathione. Since it is known that inactivation of intracellular sulfhydryl groups causes complete inhibition of the exocytotic response, it seems evident that the very strong inhibition of exocytosis by high NO concentrations is due to the reaction of NO with glutathione or with other sulfhydryl group-containing targets. (C) 1997 Elsevier Science B.V.