Evidence that the functional responses of human neutrophils occur independently of transient elevations in cyclic AMP levels.
Exposure of human neutrophils to the tripeptide formyl-methionyl-leucyl-phenylalanine (FMLP) leads to a transient, 2-3 fold elevation of adenosine-3',5'-cyclic monophosphate (cAMP) that peaks at 5-15 seconds. This cAMP transient has been hypothesized as constituting an early activation event that may be responsible for subsequent functional responses. In order to evaluate the dependence of several FMLP-stimulated functional responses on elevated cAMP levels, we utilized 9-(tetrahydro-2-furyl)adenine (SQ 22,536), a putative inhibitor of adenylate cyclase. Pretreatment of cells with SQ 22,536 (1-1000 microM) caused dose-dependent inhibition of the FMLP (0.1 microM)-induced cAMP elevation (ID50 approximately 5 microM). Similar results were observed when cells were activated by the divalent cation ionophore A23187 (20 microM). At 1000 microM, a drug concentration which completely abolished the cAMP transient, SQ 22,536 had no effect on FMLP-stimulated superoxide radical (O2-) generation, granule enzyme release, or chemotaxis and only a modest inhibitory effect on A23187-induced O2- production. These studies strongly suggest that these FMLP- and A23187-induced responses occur independently of a transient elevation of cAMP and that, in intact human neutrophils, SQ 22,536 is a non-toxic inhibitor of adenylate cyclase.
D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000262:Adenylyl Cyclases / Q000097:blood; D000001:Calcimycin / Q000494:pharmacology; D002633:Chemotaxis / Q000187:drug effects; D000242:Cyclic AMP / Q000097:blood / Q000502:physiology*; D003594:Cytoplasmic Granules / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009504:Neutrophils / Q000378:metabolism / Q000502:physiology*; D013481:Superoxides / Q000097:blood; D013997:Time Factors
D013481:Superoxides; C017759:9-(tetrahydro-2-furyl)-adenine; D000001:Calcimycin; D009240:N-Formylmethionine Leucyl-Phenylalanine; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; D000225:Adenine