The stability and metabolism of intravenously administered neurotensin in the rat

The clearance and metabolism of synthetic and tritiated ( 3H) neurotensin (NT) were studied following its intravenous injection in a pharmacologic dose (500 pmol/kg) into anesthesized rats. Immunoreactive NT (iNT), measured in a radioimmunoassay (RIA) with use of a carboxyl-(C)-terminal directed antiserum, displayed an apparent half-life ( t 1 2 ) of 0.55 min, while that measured by an amino-(N)-terminal directed antiserum had a t 1 2 of 5 min. The radiolabel from injected 3H-NT ( 3H on Tyr 3,11) had a t 1 2 of 6.5 min. High-pressure liquid chromatography of extracts of plasma obtained from the circulation 0.5–3 min after injection of NT and 3H-NT showed the presence of NT and the generation mainly of the fragments NT 1–8, NT 1–11, and NT 9–13, as well as free 3H-labeled tyrosine. The apparent half-lives of intravenously injected synthetic NT 1–8, NT 1–11 and NT 1–12 measured with the N-terminal RIA were 9, 5 and 5 min, respectively, while that for NT 9–13 was less than 0.5 min. These results indicate that exogenously injected NT is rapidly metabolized to form N-terminal fragments which are cleared more slowly than NT. These findings suggest that use of N-terminal antisera to detect the release of endogenous NT into the circulation is likely to yield measurements of the fragments NT 1–8 and NT 1–11 which thus far have been found to be biologically inactive.