Organ and plasma metabolism of neurotensin in sheep.

The metabolism of neurotensin (NT) across specific vascular beds of conscious sheep and the stability of NT in plasma have been quantitated. The nature of the metabolites has been characterized with region-specific antiserums and chromatography. NT-(1-13) was infused at 200 pmol X kg-1 X h-1 for 60 min into nine ewes, and blood samples were taken via cannulas in the aorta, pulmonary artery, portal vein, hepatic vein, renal vein, and jugular vein. Two antiserums, one directed towards the N-terminal end of NT (7852) and the other directed to the C-terminal end (C28) were used for radioimmunoassay. Pancreatic polypeptide (PP) was measured also. Using the steady-state concentrations in the aorta, the metabolic clearance rate of NT measured with C28 was 25.8 +/- 3.2 ml X kg-1 X min-1, twice that with 7852. The kidney, brain, and gut were the major organs clearing NT with a greater disappearance of C-terminal than N-terminal immunoreactivity. Gel chromatography of plasma at steady state showed that the NT immunoreactivity consisted of intact NT and N-terminal fragments; no C-terminal fragments were detected. Similarly, incubation of NT in plasma in vitro resulted in the generation of stable N-terminal fragments. The kidney was also the major organ involved in the clearance of PP both in the basal state and after stimulation by NT. Because the C-terminal end of NT is biologically active, these studies suggest that either N-terminal fragments have some unknown biological role or that NT is acting as a local hormone.