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The aim of the present study in man was to investigate the influence of cigarette smoking on basal plasma concentrations of neurotensin-like immunoreactivity (p-NTLI), as well as on fat-induced elevation of p-NTLI levels. On three separate occasions, habitual tobacco smokers either ingested fat (55 ml Intralipid 20%) or smoked three cigarettes, or ingested fat and smoked. The subjects were fasted overnight and told no to smoke during the fasting period. Smoking of one cigarette at one hour intervals (0, 60, and 120 min) did not change the p-NTLI levels (n = 6). Ingestion of fat caused a significant increase (n = 16) and when these two procedures were combined (n = 16), the mean integrated p-NTLI response (nM0-180 min) was 56% larger than the response after fat ingestion alone. The results show that cigarette smoking potentiates the fat-induced elevation of p-NTLI levels, whereas cigarette smoking per se has no effect.

The effect of ingestion of amino acids (Vamin N), glucose, and fat (Intralipid) on the concentration of neurotensin-like immunoreactivity (NTLI) in plasma was determined in 6 healthy male volunteers. After ingestion of Intralipid (55 ml, 200 mgxml-1) there was a significant increase in the plasma concentration of NTLI. The calculated integrated total NTLI response (6.7 +/- 2.5 nM over 180 min) was statistically significant. Although isocaloric amounts of Vamin and glucose also increased the plasma concentration of NTLI, these increases were not statistically significant. The data indicate that fat is an important stimulus for the release of NTLI from the small intestine. It is suggested that neurotensin, or a metabolite, in blood may be a hormone involved in the postprandial inhibition of gastric motility and gastric acid secretion elicited from the small intestine.

The actions of the tridecapeptides neurotensin and (Gln4)-neurotensin have been studied on the heart and on the blood flow in subcutaneous adipose tissue, skin and small intestine of anesthetized dogs. In addition, their possible actions have been investigated on blood glucose concentration and lipolysis in subcutaneous adipose tissue. The two peptides were found to be approximately equipotent. Intravenous infusion of 20-120 ng X kg-1 X min-1 produced slight hypotension, an initial vasodilatation in the small intestine and a delayed vasoconstriction in denervated subcutaneous adipose tissue and to a lesser extent in the skin and small intestine. At this infusion rate, neurotensin and (Gln4)-neurotensin did not elicit vasodilatation in the skin or adipose tissue and had no effect on heart rate. The delayed vasoconstriction in adipose tissue was not inhibited by local alpha-receptor blockade. Both neurotensin and (Gln4)-neurotensin increased glucose concentration in the upper dose range. No effects on lipolysis were observed, either in vivo or in vitro. These experiments show that neurotensin and (Gln4)-neurotensin have both vasodilator and vasoconstrictor actions in the peripheral vasculature but seem to be without cardiac actions. They also increase blood glucose concentration. It remains to be shown whether these actions are direct or whether some are indirectly mediated.

The effects of (D-Pro2, D-Trp7,9)-substance P, a structural analogue of substance P, were examined in two models on cerebrovascular responses to substance P(SP) in cats; in vitro using segments of the middle cerebral artery and in situ by microapplication of the peptides close to pial arterioles. (D-Pro2, D-Trp7,9)-SP in concentrations up to 6.6 x 10(-6) M was without significant effect upon isolated middle cerebral arteries under normal conditions and in arteries contracted with prostaglandin F2 alpha. SP caused concentration-dependent relaxations of middle cerebral arteries contracted by prostaglandin F2 alpha (mean +/- SE; EC50: 2.0 +/- 1.6 x 10(-9) M). The presence of (D-Pro2, D-Trp7,9)-SP shifted the concentration-response curve of SP towards higher concentrations without significantly effecting the maximum response of the arteries to SP. A relaxation by 24.2 +/- 4.0% (n = 6) was obtained in prostaglandin F2 alpha contracted arteries by increasing the potassium concentration with 2 mM in the buffer solution. This response to potassium was unaltered in the presence of 6.6 x 10(-6)M of (D-Pro2, D-Trp7,9)-SP (25.0 +/- 7.1%, n = 5). Perivascular microapplication of SP around individual pial arterioles in situ effected dose-dependent increases in vascular calibre (mean response 14.5 +/- 2% with SP, 10(-7)M). The concomitant perivascular administration of (D-Pro2, D-Trp7,9)-SP (6.6 x 10(-6)M), which alone did not alter the arteriolar calibre, attenuated significantly the cerebrovascular response to SP (mean response 1.5 +/- 3.2%). On the basis of the agonist-antagonist relation found, these observations point to the possibility of a specific SP receptor site in cerebral arteries and arterioles.

The effect of nephrectomy and ureter ligation on the concentration of endogenous plasma neurotensin-like immunoreactivity (p-NTLI) was studied in conscious rats by means of antiserum 17-8201 which detects NT (1-13) only, and antiserum 0-7709 which detects NT(1-13) and NT(1-8). The unstimulated p-NTLI concentration did not change significantly during a 25-h observation period following nephrectomy in comparison with sham operation. However, stimulation of the release of NTLI by intraduodenal administration of oleic acid (0.2 ml) resulted in significantly higher p-NTLI levels in the nephrectomized rats than in the sham operated rats. Ureter ligation did not significantly affect basal or stimulated p-NTLI. The data indicate that the kidneys play an important part in the elimination of p-NTLI released after fat ingestion.

The purpose of this study was to evaluate the pharmacological properties of a substance P (SP) analogue [D-Arg, D-Pro, D-Trp, Leu]SP as an SP antagonist. This analogue, blocked the SP-induced contractions of the isolated guinea-pig ileum and the rat urinary bladder and it exhibited no spasmogenic activity on these preparations. The affinity constant (pA2) for [D-Arg, D-Pro, D-Trp, Leu]SP versus SP was 6.31 on the guinea-pig ileum preparation and 5.30 on the rat urinary bladder preparation. The slopes of the regression lines of the Schild plots were close to unity. These data indicate that [D-Arg, D-Pro, D-Trp, Leu]SP blocks SP receptors in a simple competitive manner and suggest that there are at least two subpopulations of SP receptors. The contractions caused by the closely related tachykinins eledoisin and physalaemin were also blocked by the SP analogue. However, the slopes of the regression lines were significantly different from unity. Moreover, when tested on the hamster urinary bladder, which contracts at low concentrations of eledoisin but is rather insensitive to physalaemin and SP, [D-Arg, D-Pro, D-Trp, Leu]SP did not block the contractile actions of eledoisin or of physalaemin and SP. Compared to SP eledoisin and physalaemin may bind to SP receptors in a different manner. Eledoisin also seems to interact with receptors different from the SP receptors.

The influence of neurotensin, substance P and methionine-enkephalin (met-enkephaline) on proximal and distal colonic motility was studied in anesthetized cats. When administered i.v, at a dose of 14 pmol x kg-1 x min-1, neurotensin increased basal smooth muscle tone and antiperistaltic activity in the proximal colon. After higher doses of neurotensin the basal muscle tone also increased in the distal colon. Substance P at a dose of 17 pmol x kg-1 x min-1 selectively and powerfully stimulated the distal colon, thus causing a mass contraction pattern with a concomitant decrease in peristaltic amplitude. In the proximal part of the colon 17 pmol x kg -1 x min-1 of substance P exerted an inhibitory action on the peristaltic amplitude in animals with a high level of spontaneous activity. In addition, the basal muscle tone was slightly decreased. In animals with sluggish spontaneous activity, however, no effects were detected in the proximal colon. With increasing doses of substance P forceful contractions of the proximal colon were also registered. Met-enkephalin at a dose of 40 pmol x kg-1 x min-1 increased the smooth muscle basal tone with no effect on the peristaltic activity in the proximal or distal segments. The effect on basal tone was blocked by naloxone. Thus, neurotensin, substance P and met-enkephalin have distinct motor actions on the colon. At low doses neurotensin may stimulate the churning and mixing functions of the proximal colon. Substance P exerts its major effects on the distal part with a mass contraction response and met-enkepahlin increases the basal muscle tone equally in the proximal and distal parts of the colon.

The effect of intraduodenal administration of various types of lipids on the concentration of p-NTLI has been studied on anesthetized rats. Oleic acid, sodium oleate, triolein, linoleic acid, linolenic acid, arachidonic acid, butyric acid, liquid paraffin, phosphatidyl choline (lecithin) and saline were administered. Oleic acid, triolein, linoleic acid and linolenic acid significantly increased the integrated response of p-NTLI. The maximal concentration of p-NTLI was reached 40 min after administration of oleic acid. However after instillation of triolein, the maximal concentration was reached at 100 min which was significantly later. The results indicate that the response of p-NTLI following administration of fat into the duodenum of rats is a specific event caused by fatty acids rather than by lipophilic substances in general. Of the substances tested 18-carbon fatty acids were the most effective in increasing the concentration of p-NTLI. Shorter- or longer-chain fatty acids were less effective. The degree of unsaturation, i.e. the presence of one or more double bounds is also of importance. Triglycerides seem to be hydrolysed to fatty acids before they may bring about an increase in the concentration of p-NTLI. The charge of lipids seems to be critical since the sodium salt of oleic acid had limited effects. Arachidonic acid did not change the integrated response of p-NTLI indicating that products of cyclooxygenase and lipoxygenase pathways are not involved in the fatty acid induced release of NTLI.

Intraduodenal administration of oleic acid increased plasma neurotensin-like immunoreactivity (p-NTLI). The integrated responses to saline and oleic acid were 5.7 and 9.7 nM0-180 min, respectively. The integrated response was not significantly altered by i.v. administration of atropine, guanethidine, mepyramine, cimetidine, methysergide or a substance P antagonist, but it was abolished by hexamethonium and morphine (5.9 and 6.3 nM0-180 min, respectively). An exogenous supply of bile and pancreatic juice did not alter the integrated response in morphine- and hexamethonium-treated rats. Haloperidol significantly increased the p-NTLI response to oleic acid (13 nM0-180 min). The results suggest that the release of neurotensin is influenced by nervous pathways involving nicotinic and opioid receptors. Catecholamines and 5-HT receptors may exert an inhibitory influence on the release of NTLI.

The vasoconstrictor action of the tridecapeptide (Gln4)-neurotensin has been studied in subcutaneous adipose tissue in the inquinal region of anesthetized dogs. Close intra-arterial infusion of (Gln4)-neurotensin, 30--120 pmol X kg-1 b.wt. X min-1, elicited similar vasoconstrictions in the adipose tissue on the infusion side and on the contralateral side. This suggests that (Gln4)-neurotensin must enter the general circulation before it can elicit vasoconstriction. Removal of parts of the gastrointestinal tract did not change the vasoconstrictor response. Thus, there is no indication of release of vasoactive substances from the gastrointestinal tract by (Gln4)-neurotensin. Infusion into the portal vein elicited the same vasoconstriction in adipose tissue as the same dose administered i.v. It is suggested that the vasoconstrictor action in adipose tissue is not caused by (Gln4)-neurotensin per se. Instead, vasoactive substance(s) may be formed from (Gln4)-neurotensin.