Characterization of the inhibitory effect of [D-Trp11]-NT toward some biological actions of neurotensin in rats.

We assessed the influence of various doses of [D-Trp11]-NT on the increase of histaminemia and hematocrit, and decrease of blood pressure, caused by intravenous injections of neurotensin (NT), substance P (SP) and compound 48/80 (C48/80) in anesthetized rats. [D-Trp11]-NT was found to inhibit dose-dependently and selectively the changes of histaminemia, hematocrit and blood pressure caused by NT. Since the highest dose of [D-Trp11]-NT utilized exhibited slight NT-like activity, we tested the possibility that desensitization rather than true pharmacological antagonism was responsible for the inhibitory action of [D-Trp11]-NT toward NT. This hypothesis was verified by evaluating the influence of intravenous infusions of sub-stimulatory and slightly active doses of NT on NT-induced effects. The sub-stimulatory dose (0.1 nmoles kg-1 min-1) as well as a higher dose rate (0.2 nmole kg-1 min-1) of NT were found to inhibit markedly the changes of histaminemia, hematocrit and blood pressure evoked by bolus doses of NT, without altering the effects of C48/80 on the same parameters. These results suggest that the inhibitory action of [D-Trp11]-NT toward NT-induced changes of histaminemia, hematocrit and blood pressure could be the result of receptor desensitization rather than to a true pharmacological antagonism. The results also suggest that the sensitivity of target tissues to exogenous NT could be modulated to some extent by endogenous circulating levels of NT.