INHIBITION OF NEUROTENSIN-STIMULATED MAST-CELL SECRETION AND CARBOXYPEPTIDASE-A ACTIVITY BY THE PEPTIDE INHIBITOR OF CARBOXYPEPTIDASE-A ANDNEUROTENSIN-RECEPTOR ANTAGONIST SR-48692

Background: Neurotensin (NT), a peptide found in brain and several per ipheral tissues, is a potent stimulus for mast cell secretion and its actions are blocked by the specific NT receptor antagonist, SR 48692. Subsequent to stimulation, NT is rapidly degraded by mast cell carboxy peptidase A (CPA). In the experiments described here, we tested for th e involvement of CPA activity in the activation of mast cell secretion by the peptide, NT. Methods: Mast cells were isolated from the perito neal and pleural cavities of rats, purified over metrizamide gradients and incubated at 37 degrees C in Locke solution or Locke containing t he appropriate inhibitors. For some experiments, media derived from ma st cells stimulated by compound 48/80 were used as a source of mast ce ll CPA activity. Results: Treatment of mast cells with the highly spec ific peptide inhibitor of CPA derived from potato (PCI) inhibited hist amine release in response to NT and NT8-13 (the biologically active re gion of NT). This inhibition required some 20 min to develop and was o nly partially reversed by a 20-min wash period. PCI (10 mu M) did not inhibit histamine release in response to NT1-12,bardykinin, compound 4 8/80, the calcium ionophore, A23187, or anti-IgE serum. PCI also inhib ited mast cell CPA activity. SR 48692, a highly selective antagonist o f the brain NT receptor and of NT-stimulated mast cell secretion, also inhibited mast cell CPA activity as well as bovine pancreatic CPA act ivity in a concentration-dependent manner. Discussion: It is suggested that the mast cell binding site for NT and the active site for CPA ma y share similar characteristics. The results are discussed in terms of NT mechanism of action on the mast cell.