Interaction of cyclic GMP and cyclic AMP during neutrophil migration: involvement of phosphodiesterase type III.

In previous experiments, it was shown that migration of electropermeabilized human neutrophils induced by a combination of cGMP and cAMP markedly lower relative to that induced by cGMP or cAMP alone. However, when cGMP was replaced with 8-(para-chlorophenylthio-guanosine-3',5'-cyclic monophosphate (8-pCPT-cGMP), a metabolic stable analogue of cGMP which does not affect the activity of cGMP-regulated phosphodiesterases (PDEs), migration in the presence of cAMP was enhanced in an additive way. To investigate the role of cyclic nucleotide breakdown during neutrophil migration in more detail, specific inhibitors of phosphodiesterase type III (PDE-III) (cGMP-inhibited) were used. Milrinone and cilostamide inhibited migration induced by an optimal concentration of cAMP. This revealed that inhibition of cAMP breakdown, by prolonging the action of an otherwise optimal concentration of cAMP, led to decreased migration, in accordance with the observation that the effect of cAMP on migration of electropermeabilized neutrophils was biphasic. Furthermore, it was found that a combination of 8-pCPT-cGMP and milrinone/cilostamide could substitute for cGMP in both activating cGMP-dependent protein kinase (8-pCPT-cGMP) and inhibiting PDE-III (milrinone/cilostamide). In conclusion, evidence is presented that cGMP and cAMP could interact on the level of PDE-III during neutrophil migration.