Pepsin Treatment of Mammalian Plasma Generates Immunoreactive and Biologically Active Neurotensin-Related Peptides in Micromolar Concentrations*

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Abstract
Treatment of mammalian plasmas or sera with pepsin gave rise to extraordinary quantities (1-5 .mu.M) of immunoreactive neurotensin (NT)-related peptide(s). Although immunochemical and chromatographic analysis indicated that the peptides liberated by pepsin differed from authentic neurotensin, one of the major immunoreactive products displayed NT-like biological properties. Partially purified preparations of the immunoreactive peptides increased cutaneous vascular permeability when injected intradermally in rats and released histamine from isolated rat mast cells. The pepsin-generated peptides appeared to share the biologically active C-terminal portion of NT, since they reacted with antisera selective for this region but were not recognized by N-terminal-directed antisera. Gel permeation chromatography demonstrated the presence of two substrates in plasma which liberated iNT upon treatment with pepsin, one in the albumin fraction (mol wt, 65 K) and the other a globulin (mol wt, 350 K). A variety of other proteases and substrates failed to have this effect. These results suggest the existence of a system(s) in blood, analogous to the reninangiotensin system, for the generation of biologically active NT-related peptides.