THE ROLE OF CYCLIC-AMP AND PROTEIN-KINASE-A IN STIMULATION OF NEUTROPHIL MIGRATION BY ENDOTHELINS

The role of cAMP and cAMP-dependent protein kinase A (PKA) in endothel in (ET)-stimulated migration of human neutrophils was studied. Endothe lins caused an increase in neutrophil migration when they were applied in low (nanomolar) concentrations; stimulation of migration was eithe r predominantly chemokinetic (ET-I) or chemotactic (ET-2, ET-3). All e ndothelins, at concentrations which gave maximal stimulation of migrat ion, caused an increase of cAMP level. Two inhibitors of adenylate cyc lase, MDL-12330A and SQ-22536, completely inhibited migration activate d by ET-I, ET-2 or ET-3, indicating that cAMP generation played a deci sive role in endothelin-activated migration. The role of PKA in endoth elin-activated migration was considered. Two specific antagonists of P KA strongly inhibited endothelin-activated migration. KT-5720, an inhi bitor of PKA, also inhibited ET-activated migration, but only when ele ctroporated cells were used. The results suggest that the effect of cA MP on endothelin-activated migration was mediated by PKA.