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In dogs with innervated fundic pouches an intravenous infusion of (Gln4)-neurotensin, 60 pmol x kg-1x min-1, reduced the pentagastrin-stimulated acid secretion to 40 of the control secretory rate. After vagal denervation of the fundic pouches the same dose of (Gln4)-neurotensin did not significantly change the secretion. These findings suggest that (Gln4)-neurotensin does not act directly on parietal cells but inhibits acid secretion at a presynaptic level.

The effects of intraduodenal administration of oleic acid (5, 10, 20, and 40 ml) on gastric acid secretion stimulated by a submaximal intravenous pentagastrin infusion and on plasma concentrations on neurotensin-like plasma immunoreactivity (NTLI) were studied in 18 healthy subjects. Each volume of oleic acid or saline (controls) was tested in six subjects except the volume of 20 ml, which was given to ten subjects. Gastric acid secretion was studied for a 2-h period at 15-min intervals after intraduodenal infusion. Five milliliters oleic acid evoked a significant inhibition (29) of gastric acid secretion. Maximal inhibition by oleic acid appeared after 20 ml (43), which was significantly greater than after 10 ml. In seven duodenal ulcer (DU) patients 20 ml oleic acid evoked an inhibition of 20, which was significantly lower than in the healthy subjects. Proximal gastric vagotomy (PGV) abolished the fat inhibition in DU patients. Basal and peak NTLI concentrations after 20 ml oleic acid were significantly lower in DU patients than in healthy subjects. In DU patients there was no significant difference in the integrated response of NTLI before and after PGV. The 2-h integrated NTLI response was dependent on the administered volume of oleic acid in healthy subjects. There was a correlation between acid inhibition and the integrated response of NTLI in healthy subjects. This suggests that immunoreactive neurotensin may be involved in the oleic-acid-induced inhibition of gastric acid secretion. Neurotensin, or a neurotensin metabolite, apparently exerts its inhibitory effect at a synaptic level, which explains the finding that oleic acid did not inhibit gastric acid secretion after PGV. Neurotensin may have a physiological role as a hormone with enterogastrone functions.

Electrical stimulation of the cervical vagus nerve in anesthetized guinea pigs induced a rapid increase in respiratory insufflation pressure, suggesting increased airway resistance. After intravenous administration of a substance P (SP) antagonist, [D-Arg1,D-Pro2,D-Trp7,9,Leu11]SP, the insufflation pressure response to vagal stimulation was reduced by 78% while the cardiovascular effects were unchanged. Histamine receptor-blocking agents were used to inhibit the effects of histamine release induced by the SP-antagonist. [D-Arg1,D-Pro2,D-Trp7,9,Leu11]SP also reduced the increase in insufflation pressure caused by intravenous SP or capsaicin. The long-lasting noncholinergic contraction of the main and hilus bronchi induced by field stimulation in vitro, as well as the contractile effects of SP and capsaicin, were also blocked by the SP antagonist. The cholinergic contractions and the noncholinergic tracheal relaxation on field stimulation in vitrowere, however, not blocked by the antagonist. Vagal stimulation in vivoalso increased vascular permeability in the respiratory tract and esophagus, causing a subepithelial edema as indicated by Evans blue extravasation. Previous treatment with [D-Arg1,D-Pro2,D-Trp7,9,Leu11]SP inhibited the permeability increase induced by both vagus nerve stimulation and exogenous SP. SP release from vagal sensory nerves was indirectly shown by reduction in the bronchial levels of SP after nerve stimulation in vivo. The data suggest that a major portion of the vagally or capsaicin-induced increase in smooth muscle tone is caused by SP release from sensory neurons. In addition, activation of vagal SP-containing sensory nerves induces local edema. Tracheobronchial afferent SP-containing C fibers may thus exert local control of smooth muscle tone and vascular permeability in normal and pathophysiological conditions.

Intraduodenal administration of oleic acid has previously been shown to inhibit gastric acid secretion induced by pentagastrin in man. This inhibition was dose-dependent and significantly correlated to a rise in plasma concentration of neurotensin-like immunoreactivity (NTLI). Maximal inhibition occurred with a volume of oleic acid of 20 ml. In the present study intraduodenal instillation of 20 ml of oleic acid inhibited acid secretion evoked by sham feeding in healthy subjects but did not significantly inhibit the near-maximal acid secretion stimulated by the histamine analogue betazole. The inhibition of acid secretion induced by sham feeding was the same (about 45) as the inhibition of pentagastrin-stimulated secretion. Plasma NTLI rose significantly in both the sham feeding and betazole experiments and peaked at about 145 pM. The results are in agreement with the inhibitory characteristics of neurotensin and support the hypothesis that the inhibition of gastric acid secretion by small amounts of intestinal fat is at least partly mediated by neurotensin.

The effects of heparin, histamine, and Compound 48/80 on the release of free fatty acids (FFA), glycerol, and venous plasma lipolytic activity (VPLA) from the isolated perfused canine subcutaneous adipose tissue in situwas studied. Intra-arterial administration of heparin with dosages between 5 to 500 μg produced an increase in VPLA release which was dose dependent. The VPLA release was decreased after repeated injection of heparin. Heparin administration did not alter the release of FFA and glycerol. Histamine and Compound 48/80 increased FFA and glycerol release, but produced no effect on VPLA release. The results do not support the contention concerning a possible role of mast cell heparin in the regulation of lipid metabolism in canine subcutaneous adipose tissue but confirm the previous findings that mast cell histamine may exert some effect in the mobilization of FFA.

Nerve fibres containing substance P (SP) are widely distributed in the body1–3and seem to innervate autonomic ganglia, blood vessels, epithelial structures and smooth muscle. SP stimulates secretion from exocrine glands, causes vasodilation and contracts non-vascular smooth muscle4. The presence of SP in primary sensory neurones has lent support to the view that it is associated with sensory nerve conduction, conceivably as a transmitter5, and that it is a causative factor in the ‘irritative’ response to antidromic stimulation of sensory nerves6. Gut smooth muscle contracts in response to non-cholinergic, non-adrenergic nervous stimulation7,8, and it has been suggested that SP acts as an excitatory transmitter in intramural neurones in the gut wall2,3,9,10. Recently, a series of synthetic analogues of SP with antagonist activity to SP has been developed11,12. We report here that a new analogue, (D-Pro2, D-Trp7,9)-SP, exercises a specific, possibly competitive antagonism to SP. While being a partial agonist it antagonized the contractile response to applied SP and to non-cholinergic, non-adrenergic nerve stimulation in the isolated guinea pig taenia coli and rabbit iris sphincter pupillae muscle, suggesting that SP, or a closely related peptide, is indeed a motor excitatory transmitter. In contrast, (D-Pro2, D-Trp7,9)-SP did not inhibit the contractile response to non-cholinergic, non-adrenergic nerve stimulation of smooth muscle from the guinea pig urinary bladder.

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