PHARMACOLOGICAL HETEROGENEITY OF NEUROTENSIN RECEPTORS - AN IN-VITRO STUDY

Neurotensin (NT), a linear tridecapeptide, has been shown to exert a v ariety of biological effects in the periphery and in the central nervo us system. The aim of the present study was to characterize the NT rec eptors mediating the contractions of two isolated organs, the rat stom ach strip and the guinea pig ileum. More than 20 compounds, peptides, nonpeptides, or pseudopeptides, were tested for their agonistic and an tagonistic effects against NT and a series of potent analogs or fragme nts. Receptors were characterized using the two classical criteria sug gested by Schild, the order of potency of agonists and the affinity of antagonists. The results shown in this study indicate that the contra ctions of the guinea pig ileum in response to NT are mediated by acety lcholine and prostaglandins because they are blocked by atropine and i ndomethacin. The contractions induced by NT in the rat stomach are not influenced by atropine, indomethacin, methysergide, and diphenhydrami ne and may result from the direct activation of smooth muscle receptor s. Differences in the order of potency of agonists were also found bet ween the two preparations: in the rat stomach strip, the order of pote ncy was AcNT(8-13) > Arg-NT(8-13) > Lys-NT(8-13) > NT = NT(8-13) and i n the guinea pig ileum was Arg-NT(8-13) > AcNT(8-13) > NT = NT(8-13) > Lys-NT(8-13). The nonpeptide antagonist SR 48692 was shown to possess higher apparent affinity for the rat stomach functional sites (pA(2) 8.0) than for those of the guinea pig ileum (pA(2) 6.45). The results presented in this paper suggest that two different pharmacological ent ities may subserve the myotropic effect of NT and some analogs and fra gments in the gastrointestinal tract of the guinea pig and the rat.