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We have assessed the influence of acute bilateral nephrectomy, of captopril and saralasin, on the hypotensive activity of neurotensin (NT) and of various hypotensive drugs in pentobarbital-anesthetized rats. The results show that the hypotensive activity of NT and of compound 48/80 (C48/80), in contrast to that of histamine, of 5-hydroxytryptamine and of hexamethonium, is markedly reduced, especially for NT, in nephrectomized as compared to sham operated rats. The pretreatment of rats with captopril (10 mg kg-1, i.v.) or with saralasin (20 micrograms kg-1 min-1, i.v.) was found to inhibit significantly the hypotensive activity of NT and of C48/80. Adrenalectomy restored partially the hypotensive activity of NT in nephrectomized rats. The potent vasopressin antagonist [d(CH2)5 Tyr(Me)AVP] did not alter the refractoriness of nephrectomized rats to the hypotensive activity of NT. Neither nephrectomy nor saralasin were found to interfere with the ability of NT or of C48/80 to evoke an increase of plasma histamine level or of the hematocrit. The results were interpreted as an indication that NT produces part of its hypotensive effect in anesthetized rats by reducing the activity of the renin angiotensin system. The results also suggest that part of the refractoriness of nephrectomized rats to the hypotensive activity of NT could be due to the release of catecholamines from adrenal glands by NT. Endogenous vasopressin does not appear to contribute to the refractoriness of nephrectomized rats to the hypotensive action of NT.

We have tested the effects of intravenous injections of substance P (SP), bradykinin (BK), somatostatin (SS) and vasoactive intestinal peptide (VIP) on the blood pressure, histaminemia and hematocrit in pentobarbital-anesthetized rats. The four peptides elicited a decrease of the mean arterial blood pressure which varied both in amplitude and in duration depending both on the peptide and on the doses utilized. The hypotensive effects of SP and VIP were more persistent than those caused by BK or SS. Only SP evoked an increase of histaminemia. Both SP and BK caused an increase of hematocrit. The change of hematocrit was more prominent and of longer duration after Sp than after BK. Pretreatment of rats with the antiinflammatory drug dexamethasone inhibited markedly the changes of blood pressure, histaminemia and hematocrit caused by SP. The hypotensive effects of BK, SS and VIP as well as the transient change of hematocrit evoked by BK were not affected by dexamethasone. The results suggest that part of the hypotensive activity and changes of hematocrit evoked by SP in rats is due to the release and action of histamine and possibly of other vasoactive substances, of mast cell origin. The results also indicate that mast cell mediators, particularly histamine, are unlikely to be instrumental in the hypotensive activity of BK, SS or VIP in rats.

Intracarotid infusions of neurotensin (NT) into the isolated, perfused head of rats trigger concentration-dependent histamine and 5-hydroxytryptamine (5-HT) release from the perfused organ. The secretory event was accompanied by a concentration-dependent rise in perfusion pressure and facilitation of edema formation. The three NT effects were markedly reduced in heads derived from rats pretreated with high doses of compound 48/80 to produce mast cell depletion. The vasoconstrictor response to NT was greatly attenuated by the 5-HT receptor antagonist methysergide but unaffected by antihistaminic drugs. The results were interpreted as an indication that NT stimulates histamine and 5-HT release from mast cells of the rat perfused head. The results also suggest that the vasoconstrictor response to NT in the rat head is mediated by mast cell 5-HT. The potentiation of edema formation by NT was attributed to the action of mast cell mediators (most likely histamine and 5-HT) released by NT on microvessels.

In the present study, we evaluated and compared effects of BB, GRP and related C-terminal fragments on body temperature and grooming. Peptides were administered into the left cerebral ventricle of rats. Body temperature and grooming behavior were assessed over a 2 hr period following injections. All peptides significantly decreased body temperature and increased grooming behavior of animals. However, important differences in potency, efficacy and duration of action were found between BB, GRP and their fragments.

Intravenous injections of neurotensin (NT) (0.5, 1 and 2 nmoles kg-1) evoked dose-dependent increases in histaminemia and hematocrit, and marked hypotensive effect, in anesthetized rats. The increase of plasma histamine was rapid in onset (within sec), peak plasma histamine being reached in less than 2 min. The decline of plasma histamine was gradual and almost complete 15 min after injection of NT. The hematocrit increased slowly, maximum values being obtained 5-10 min after injection of NT, and it persisted throughout the period of observation. The hypotensive effect of NT was rapid in onset and of prolonged duration. Compound 48/80, a well known histamine liberator and mast cell depletor, produced variations of blood pressure, of hematocrit and of plasma histamine very similar to those elicited by NT. Pretreatment of rats with cromoglycate, a well known mast cell stabilizer, or with dexamethasone, inhibited markedly the changes of histaminemia, of hematocrit and of blood pressure evoked by NT and compound 48/80. The results clearly suggest that the effects of NT on blood pressure and on vascular permeability in rats are mediated to some extent by mast cell histamine. Hexamethonium, a ganglion blocker, inhibited slightly the effect of NT on histaminemia but it did not block NT-induced changes of hematocrit. However, the hypotensive effect of NT was severely blocked in hexamethonium-treated rats. These results were interpretated as an indication that hexamethonium prevents NT-induced hypotension not merely by reducing the mobilization of mast cell histamine by NT but most likely by interfering with the mechanism by which NT and/or its mast cell mediators produce their effects on blood pressure.

The potency of several peptides and drugs as histamine liberators was assessed using the rat isolated hind limb preparation. Neurotensin (NT) and compound 48/80 (C48/80) were effective in concentrations as low as 10(-9) M and 10(-8) M, respectively. Threshold concentrations of vasoactive intestinal peptide (VIP) and substance P (SP) varied between 5 X 10(-7) to 5 X 10(-6) M while somatostatin (SS) was barely active at 6 X 10(-6) M. No histamine release could be detected following the use of high concentrations of thyrotropin releasing hormone (TRH) (6 X 10(-6) M), dynorphin (DYN) (6 X 10(-6) M) bradykinin (BK), des-Arg9-BK or bombesin (BB) (at 10(-5) M). Poly-L-Lysine and the calcium ionophore A23187 were about 100 times less active than NT. Concanavalin A (Con A) was inactive at 10(-6) M. These results indicate that NT is more potent (on a molar basis) as histamine liberator in the rat hind limb preparation (which contains a large population of cutaneous and subcutaneous mast cells) than any of the other compounds tested. Histamine release by NT was inhibited by preexposure of the rat hind limb mast cells to a high concentration of SP (1.5 X 10(-6) M). This result adds further support to the hypothesis suggesting that NT and SP might share a common mechanism of action and/or act through common receptors at least in rat mast cells.

We have previously reported that intracameral (I.C.) administration of neurotensin (NT) potently induces a time- and dose-dependent miosis in rabbits. This study was designed to determine structure-function relationships for NT-induced miosis. NT and twelve different fragments and analogs of NT, and the structurally-unrelated peptides beta-endorphin (beta-end), somatostatin (SRIF) and thyrotropin-releasing hormone (TRH) were tested in a dose equimolar to 30 micrograms of NT for their effects on pupillary diameter (PD) in rabbits. In confirmation of previous findings, NT produced significant miosis. Followed in order of duration of effect were D-Trp11-NT, D-Tyr11-NT, the N-terminal fragment NT1-12, [Gln4] - NT and NMe-NT. The N-terminal fragment NT1-8, D-Arg8-NT, and D-Phe11-NT were weakly active. In addition, the initial N-terminal fragment NT1-6 and the C-terminal fragments NT8-13 and NT9-13 did not affect PD. D-Pro10-NT, beta-end, SRIF, and TRH were totally ineffective. The results of this investigation contribute to support a role for NT on regulation of pupillary function, and suggest that the midportion of NT appears to be critical for the expression of NT-induced miosis.

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.