Differential inhibition and potentiation of chemoattractant-induced superoxide formation in human neutrophils by the cell-permeant analogue of cyclic GMP, N2,2'-O-dibutyryl guanosine 3':5'-cyclic monophosphate

Ervens, J.; Schultz, G.; Seifert, R.

Naunyn-Schmiedeberg's Archives of Pharmacology 343(4): 370-376


ISSN/ISBN: 0028-1298
PMID: 1649410
Accession: 007210305

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Human neutrophils possess a superoxide (O2-)-forming NADPH oxidase which is activated by the chemoattractants, N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMet-Leu-Phe), complement C5a, platelet-activating factor and leukotriene B4. We studied the roles of cAMP and cGMP in the regulation of O2- formation using the cell-permeant analogues of cyclic nucleotides, N6,2'-O-dibutyryl adenosine 3':5'-cyclic monophosphate (Bt2cAMP) and N2,2'-O-dibutyryl guanosine 3':5'-cyclic monophosphate (Bt2cGMP). Bt2cAMP inhibited O2-formation induced by these chemoattractants to similar extents. Bt2cGMP as low as 10 .mu.mol/l significantly inhibited O2- formation induced by fMet-Leu-Phe at a submaximally effective concentration (50 nmol/l) and Bt2cGMP was more effective in diminishing O2- formation than Bt2cAMP. In contrast, Bt2cGMP did not affect O2- formation induced by fMet-Leu-Phe at a maximally effective concentration (1 .mu.mol/l). Bt2cGMP (0.1 and 1 mmol/l) enhanced O2- formation induced by 0.1 .mu.mol/l C5a by 23% and 49%, respectively, and Bt2cGMP antagonized inhibition of O2- formation caused by Bt2cAMP. Bt2cGMP inhibited platelet-activating factor-induced O2- formation to a lesser extent than Bt2cAMP and had no effect on that induced by leukotriene B4. Bt2cAMP and Bt2cGMP had no effect on O2- formaiton induced by NaF, .gamma.-hexachlorocyclohexane, phorbol myristate acetate, A 23187 and arachidonic acid. Our data suggest that: 1. Bt2cAMP generally inhibits chemoattractant-stimulated O2- formation. 2. Bt2cGMP inhibits fMet-Leu-Phe- and platelet-activating factor-stimulated O2- formation but potentiates C5a-induced O2- formation. 3. The lack of effect of cyclic nucleotides on O2- formation induced by agents other than receptor agonists indicates that cAMP and cGMP modulate early steps of the signal transduction processes initiated by chemoattractants.