Somatostatin as a mediator of the effect of neurotensin on pentagastrin-stimulated acid secretion in rats

Neurotensin and somatostatin have both been shown to inhibit gastric acid secretion, but no interaction between these peptides has been demonstrated. To determine whether somatostatin might be a mediator of neurotensin's effect on pentagastrin-stimulated gastric acid secretion, we performed the following three experiments. First, we collected 0.2-ml samples of portal venous blood as frequently as every 5 min, and we confirmed a significant release of somatostatin-like immunoreactivity into portal venous blood during neurotensin-induced inhibition of acid secretion. This release of somatostatin-like immunoreactivity and inhibition of acid secretion were only seen in pentobarbital-anesthetized rats, but no sustained release of somatostatin-like immunoreactivity or inhibition of acid secretion occurred in urethane-anesthetized animals. In the second experiment, we analyzed portal plasma by high pressure liquid chromatography, and found that portal somatostatin-like immunoreactivity in blood collected during neurotensin infusion was composed of a single peak corresponding to somatostatin-14. In the third experiment, we found that infusion of antibody to somatostatin prevented neurotensin from inhibiting pentagastrin-stimulated acid secretion. Taken together, these data show that somatostatin, possibly from the stomach itself, is a necessary mediator of neurotensin's inhibitory effect in pentobarbital-anesthetized rats.     

Effects of L-glutamic acid on acid secretion and mucosal blood flow in the rat stomach

The effect of intravenous administration of L-glutamic acid (L-Glu) on gastric acid secretion and gastric mucosal blood flow (GMBF) in anesthetized rats were investigated. Infusion with synthetic L-Glu alone had no effect on spontaneous acid secretion. However, L-Glu reduced histamine- (2 mg/kg/hr) or oxotremorine- (1 microg/kg/hr) stimulated acid secretion, whereas L-Glu had no effect on acid secretion induced by pentagastrin (8 microg/kg/hr). Furthermore, this inhibitory effect of L-Glu on histamine- or oxotremorine-stimulated acid secretion was blocked by 6,7-dinitroquinoxaline-2,3-dione (DNQX), a non-NMDA receptor antagonist. The effect of L-Glu on gastric mucosal microcirculation in the anesthetized rats was evaluated by using Laser Doppler Flowmetry (LDF). The results showed that L-Glu did not significantly reduce both mucosal and serosal blood flow in stomach. No significant modulatory effect on histamine- or oxotremorine-stimulated increase in GMBF was noted after infusion with L-Glu. It is concluded that L-glutamic acid is capable of the modulating of gastric acid secretion via ionotropic non-NMDA receptors, but do not affect on GMBF. However, L-glutamic acid showed no effect on acid secretion by itself.     

Gastric secretion and gastrin under progressive doses of somatostatin-14 and -28 administered intraperitoneally to the rat

The actions of progressive doses of intraperitoneally (IP) administered somatostatin-14 (SS-14) and -28 (SS-28) on gastric secretion (acid, pepsin) and mucosal blood flow (MBF) were studied in conscious gastric fistula rats both under basal conditions and under additional administration of pentagastrin. Also, somatostatin-like immunoreactivity was measured in aortal blood in all groups as well as aortal gastrin levels under basal conditions. IP infusion of equimolar doses of SS-14 and SS-28 resulted in an equal and dose-dependent inhibition of basal as well as pentagastrin-stimulated gastric acid secretion. MBF was reduced by either peptide both in the basal and pentagastrin experiments. Under basal conditions pepsin secretion was significantly increased by infusion of SS-14 at the higher doses, by infusion of SS-28 only at the intermediate dose (3.1 nmole kg-1.hr-1). In the pentagastrin experiments, low and intermediate doses of SS-14 tended to lower pepsin outputs but the highest dose of SS-14 stimulated pepsin secretion, whereas SS-28 had no effect on pepsin. Administration of SS-28 inhibited gastrin only at the highest dose (12.3 nmole kg-1.hr-1), and SS-14 had no influence at all on gastrin. After IP infusion of both peptides, plasma SLI rose dose-dependently under basal and stimulated conditions. Gel chromatography indicated an in-vivo conversion of SS-28 to SS-14 or intermediate fragments. It is concluded that SS-14 and SS-28 delivered by IP infusion, inhibit basal and stimulated gastric acid equally in the rat without suppressing gastrin. The mechanism underlying SS-mediated pepsin stimulation is unknown.     

Gastric acid secretion in streptozotocin-diabetic rats--different responses to various secretagogues.

We compared gastric acid secretion in response to various stimuli in normal and streptozotocin (STZ)-induced diabetic rats, in an attempt to characterize the alteration of acid secretory response in diabetic conditions. Animals were injected STZ (70 mg x kg(-1), i.p.) and used after 5 weeks of diabetes with blood glucose > 350 mg x dL(-1). Under urethane anesthesia, a rat stomach was mounted on an ex vivo chamber, perfused with saline and acid secretion was measured at pH 7.0 using a pH-stat method and by adding 100 mM NaOH. The acid secretion was stimulated by i.v. infusion of either histamine (4 mg x kg(-1) x h(-1)), pentagastrin (60 microg x kg(-1) x h(-1)) or carbachol (20 microg x kg(-1) x h(-1)) or i.v. injection of YM-14673 (0.3 mg x kg(-1)), an analog of thyrotropin-releasing hormone, or vagal electrical stimulation (2 ms, 3 Hz, 0.5 mA). In normal rats, gastric acid secretion was increased in response to either histamine, pentagastrin, carbachol, YM-14673 or electrical vagal stimulation. In STZ diabetic rats, however, changes in acid secretion varied depending on the stimuli; the acid secretory responses to histamine remained unchanged, those to YM-14673 and vagal electrical stimulation significantly decreased, but the responses to both pentagastrin and carbachol were significantly enhanced as compared to normal rats. Luminal release of histamine in response to both pentagastrin and carbachol was increased in STZ-diabetic rats as compared to normal animals. The altered acid secretory responses in STZ diabetic rats were partially reversed by daily injection of insulin with amelioration of high blood glucose levels. These results suggest that STZ-diabetic rats showed different changes in gastric acid secretory responses to various stimuli; no change in response to histamine, a decrease to both YM-14673 and vagal electrical stimulation and an increase to both pentagastrin and carbachol. The increased acid secretory response may be associated with an enhanced release of mucosal histamine, while the decreased response may be due to vagal neuropathy.     

Inhibition of gastric acid secretion and mucosal blood flow induced by intraventricularly applied neurotensin in rats

To investigate the central effect of neurotensin in gastric functions, changes in gastric acid secretion and mucosal blood flow (MBF) following administration were examined in rats anesthetized with urethane. Neurotensin in doses 1–10 μg/animal injected into the lateral ventricle decreased the basal value of both gastric acid output and MBF. This effect of neurotensin on these gastric parameters was completely blocked by pretreatment of animals with reserpine (2 mg/kg, i.p., 24 hr) or 6-OH-dopamine (250 μg/animal, intraventricularly, 10–14 days). These results indicate that exogenously applied neurotensin induces an inhibition of gastric functions by a central mechanism and suggest that an interaction exists between central catecholamines and the effect of neurotensin on gastric functions.     

Inhibition of pentagastrin-stimulated gastric acid secretion by intraileal administration of bile and elevation of plasma concentrations of gut glucagon-like immunoreactivity in anesthetized dogs

The effects of intraileal administration of bile on gastric acid secretion stimulated by a submaximal dose of intravenous pentagastrin infusion and on plasma concentrations of gut glucagon-like immunoreactivity (gut GLI) were studied in anesthetized dogs. Gastric acid secretion was measured for a 2-h period at 15-min intervals before and after intraluminal instillation of test solutions. 100 ml of canine bladder bile diluted to 10% in saline evoked a significant inhibition (20%) of gastric acid secretion. The inhibition of gastric acid secretion was accompanied by an elevation of plasma concentration of gut GLI, whereas saline instillation (in controls) caused no responses. Although the inhibition of gastric acid secretion and the elevation of plasma gut GLI are parallel phenomena, gut GLI can be reasonably postulated as one of the candidate mediators of bile-induced inhibition of gastric acid secretion, since its structurally related peptides, pancreatic glucagon, glicentin and oxyntomodulin have been reported as inhibitors of gastric acid secretion.     

Neurotensin inhibition of gastric exocrine secretions in the cat

The gastric exocrine inhibitory activities of neurotensin were characterized in conscious cats prepared with gastric fistulae. Neurotensin was a potent inhibitor of pentagastrin-stimulated pepsin secretion (ID50, approx. 0.3 mumol . kg-1 . h-1) but was approximately 60 times less potent against acid secretion. Neurotensin did not significantly reduce submaximal histamine-stimulated acid or pepsin secretions. the total 2 h acid and pepsin outputs in response to insulin-hypoglycaemia were not reduced by neurotensin, although the peak 15-min outputs were reduced. The reduction in peak secretion was possibly related to neurotensin antagonism of the ability of insulin to lower blood glucose concentrations. Neurotensin alone was not hyperglycaemic when given as an intravenous infusion. Two C-terminal fragments of neurotensin, the dodecapeptide and nonapeptide, inhibited pentagastrin-stimulated pepsin secretion, but were less potent than neurotensin. The observations with the C-terminal fragments indicate that the major determinants of gastric exocrine inhibitory activity of neurotensin reside in its C-terminal; this agrees with observations on other biological activities of neurotensin. The reduced potency of the dodecapeptide indicates the importance of the N-terminal pyroglutamyl residue for full gastric exocrine inhibitory activity.     

第三脑室注射组胺及其受体激动剂对五肽促胃液素诱导...

The present study shows the dual effects of intraventricularly injected histamine (0.25-2.0 micrograms/5 microliters) on pentagastrin-induced gastric acid secretion. Male Wistar rats weighing 200-300 g were anesthetized with intraperitoneal sodium pentobarbital. Gastric acid was continuously washed out with 37 degrees C saline solution by means of a perfusion pump. On the background of continuous intravenous infusion of pentagastrin [7.5 micrograms/(kg.h),] histamine (0.25 microgram/5 microliters) or 2-pyridylethylamine (PEA, 10 micrograms/5 microliters), a H1-receptor agonist, was injected into the third ventricle through a chronically implanted canula. The acid output decreased 10 min after injection and did not recover at 90 min. When the dose of histamine was increased to 1.0 micrograms or 2.0 micrograms, dual effects appeared. The acid output decreased respectively in 73% or 50% of the animals, while in the rest 27% and 50% of the animals, the acid output increased. H2-receptor agonist dimaprit (10 micrograms/5 microliters, i.c.v.) or impromidine (0.1 micrograms/5 microliters, i.c.v.) had no pronounced effect on pentagastrin-induced acid secretion. Pretreatment with diphenhydramine (16 micrograms/0.2 ml or 32 micrograms/0.2 ml, i.m.) abolished the inhibitory effect of histamine and PEA on acid secretion. These results suggest that histamine may be involved in the central regulation of gastric acid secretion, and the inhibitory effect may be mediated by H1-receptors in the brain. The mechanism underlying the production of the dual effects of histamine is unknown.     

Central action of somatostatin analog, SMS 201-995, to stimulate gastric acid secretion in rats

The effects of intracisternal and intravenous injections of the somatostatin analog, SMS 201-995, on gastric acid secretion were investigated in rats with pylorus ligation or gastric cannula. Intracisternal injection of SMS 201-995 induced a dose-related (0.1-0.3 microgram) and long-lasting stimulation of gastric acid output with a peak response at 3 h postinjection in conscious, pylorus-ligated rats. Intracisternal SMS 201-995 increased histamine levels in the portal blood, whereas plasma gastrin levels were not modified. Atropine, cimetidine and adrenalectomy abolished the stimulatory effect of intracisternal SMS 201-995 (0.3 microgram). SMS 201-995 (0.03 microgram), microinjected unilaterally into the dorsal vagal complex, increased gastric acid output in urethane anesthetized rats. SMS 201-995, injected intravenously at 0.5 microgram, did not alter gastric secretion, whereas higher doses (5-20 micrograms) resulted in a dose-related inhibition of gastric acid secretion in conscious pylorus-ligated rats. These data indicate that SMS 201-995, a selective ligand for somatostatin-1 receptor subtype, induces a centrally mediated stimulatory effect on gastric acid secretion in rats. The central action involves the parasympathetic system, muscarinic and H2 receptors as well as adrenal-dependent pathways.     

Capsaicin inhibits the pentagastrin-stimulated gastric acid secretion in anaesthetized rats with acute gastric fistula.

The effect of capsaicin on basal and pentagastrin-stimulated gastric acid secretion was investigated in the urethane anaesthetized acute gastric fistula rat. Gastric acid secretion was measured by flushing of the gastric lumen with saline every 15 min or by continuous gastric perfusion. Capsaicin given into the rat stomach at 120 ng x mL(-1) prior to pentagastrin (25 microg x kg(-1), iv) reduced gastric acid secretory response to pentagastrin by 24%. Intravenous (iv) capsaicin (0.5 microg x kg(-1)) did not reduce the pentagastrin-stimulated gastric acid secretion. After topical capsaicin desensitization (3 mg x mL(-1)), basal gastric acid secretion and that in response to pentagastrin (25 microg x kg(-1), intraperitonaeally) was unaltered compared with the control group. Data indicate that topical capsaicin inhibits gastric acid secretion stimulated with pentagastrin in anaesthetized rats.     

Stimulatory effects of endogenous and exogenous nitric oxide on gastric acid secretion in anesthetized rats

We previously reported the stimulatory effect of endogenous nitric oxide (NO) on gastric acid secretion in the isolated mouse whole stomach and histamine release from gastric histamine-containing cells. In the present study, we investigated the effects of endogenous and exogenous NO on gastric acid secretion in urethane-anesthetized rats. Acid secretion was studied in gastric-cannulated rats stimulated with several secretagogues under urethane anesthesia. The acid secretory response to the muscarinic receptor agonist bethanechol (2 mg/kg, s.c.), the cholecystokinin(2) receptor agonist pentagastrin (20 microg/kg, s.c.) or the centrally acting secretagogue 2-deoxy-D-glucose (200 mg/kg, i.v.) was dose-dependently inhibited by the NO synthase inhibitor N(omega)-nitro-L-arginine (L-NNA, 10 or 50 mg/kg, i.v.). This inhibitory effect of L-NNA was reversed by a substrate of NO synthase, L-arginine (200 mg/kg, i.v.), but not by D-arginine. The histamine H(2) receptor antagonist famotidine (1 mg/kg, i.v.) completely inhibited the acid secretory response to bethanechol, pentagastrin or 2-deoxy-D-glucose, showing that all of these secretagogues induced gastric acid secretion mainly through histamine release from gastric enterochromaffin-like cells (ECL cells). On the other hand, histamine (10 mg/kg, s.c.)-induced gastric acid secretion was not inhibited by pretreatment with L-NNA. The NO donor sodium nitroprusside (0.3-3 mg/kg, i.v.) also dose-dependently induced an increase in acid secretion. The sodium nitroprusside-induced gastric acid secretion was significantly inhibited by famotidine or by the soluble guanylate cyclase inhibitor methylene blue (50 mg/kg, i.v.). These results suggest that NO is involved in the gastric acid secretion mediated by histamine release from gastric ECL cells.     

Dual action of prostaglandin E2 on gastric acid secretion through different EP-receptor subtypes in the rat

We examined the role of prostaglandin E (EP) receptor subtypes in the regulation of gastric acid secretion in the rat. Under urethane anesthesia, the stomach was superfused with saline, and the acid secretion was determined at pH 7.0 by adding 50 mM NaOH. The acid secretion was stimulated by intravenous infusion of histamine or pentagastrin. Various EP agonists were administered intravenously, whereas EP antagonists were given subcutaneously 30 min or intravenously 10 min before EP agonists. PGE(2) suppressed the acid secretion stimulated by either histamine or pentagastrin in a dose-dependent manner. The acid inhibitory effect of PGE(2) was mimicked by sulprostone (EP(1)/EP(3) agonist) but not butaprost (EP(2) agonist) or AE1-329 (EP(4) agonist). The inhibitory effect of sulprostone, which was not affected by ONO-8711 (EP(1) antagonist), was more potent against pentagastrin- (50% inhibition dose: 3.6 mug/kg) than histamine-stimulated acid secretion (50% inhibition dose: 18.0 mug/kg). Pentagastrin increased the luminal release of histamine, and this response was also inhibited by sulprostone. On the other hand, AE1-329 (EP(4) agonist) stimulated the acid secretion in vagotomized animals with a significant increase in luminal histamine. This effect of AE1-329 was totally abolished by cimetidine as well as AE3-208 (EP(4) antagonist). These results suggest that PGE(2) has a dual effect on acid secretion: inhibition mediated by EP(3) receptors and stimulation through EP(4) receptors. The former effect may be brought about by suppression at both parietal and enterochromaffin-like cells, whereas the latter effect may be mediated by histamine released from enterochromaffin-like cells.     

Pharmacological evidence for the involvement of multiple calcitonin gene-related peptide (CGRP) receptors in the antisecretory and antiulcer effect of CGRP in rat stomach.

We have investigated the effect of the C-terminal fragment of human calcitonin gene-related peptide (human-CGRP8-37), a CGRP antagonist, on alpha-CGRP and salmon Calcitonin (sCT)-induced inhibition of gastric acid secretion stimulated by pentagastrin (24 nmol kg-1 h-1 i.v.) and gastric lesions induced by acetylsalycilic acid (ASA; 25 mM) in rats anaesthetized with urethane. Close intra arterial infusion of alpha-CGRP (2-5 nmol kg-1) and sCT (5 nmol kg-1) produced a reduction in gastric acid hypersecretion induced by pentagastrin. The concomitant infusion with human-CGRP8-37 (10 nmol kg-1) reversed the effect of both agonists. ASA-ulcers were reduced in a dose-dependent manner by infusion of alpha-CGRP (1-2 nmol kg-1 i.a.), but not by sCT (10 nmol kg-1 i.a.). Human-CGRP8-37 at a dose of 10 nmol kg-1 i.a. was unable to reverse the alpha-CGRP antiulcer effect. An higher dose of human-CGRP8-37 (50 nmol kg-1 i.a.) showed agonistic properties reducing ASA ulcers. These results suggest that the inhibitory effects of alpha-CGRP on stimulated acid secretion and aspirin ulcers are mediated by different mechanisms and/or different receptors.     

Diverse effects of phytohaemagglutinin on gastrointestinal secretions in rats.

Kidney bean lectin phytohaemagglutinin (PHA) is known for its binding capacity to the small intestinal surface inducing marked hyperplasia and hypertrophy and an increased pancreatic function. Recent observations indicate that PHA is able to attach to gastric mucosal and parietal cells. Therefore, we compared the effects of PHA on gastric acid secretion, and pancreatic amylase secretion in rats. To study gastric secretion in conscious animals, rats were surgically prepared with chronic stainless steel gastric cannula and with indwelling polyethylene jugular vein catheter. Acid secretion was determined by titration of the collected gastric juice to pH 7.0. Similar studies were performed to investigate the effect of PHA on pancreatic enzyme secretion in conscious rats supplied with pancreatic cannula. Pancreatic enzyme secretion was also studied in rats anesthetized with either halothane or urethane. In conscious rats PHA significantly inhibited basal acid secretion when compared to vehicle-treated controls. The effect was dose-dependent and reversible. On the other hand, given in the same doses as in the acid-secretory studies, PHA stimulated pancreatic amylase secretion in rats prepared with chronic pancreatic cannula. This effect was blocked by devazepide, a CCK-A receptor antagonist. In halothane-anesthetized rats PHA administration increased pancreatic amylase secretion, too. During urethane anesthesia, however, the stimulatory effect of PHA was not observed. These results provide evidence that intragastric PHA treatment induces opposite effects on gastric acid secretion and pancreatic enzyme secretion: it is a potent inhibitor of acid output, and a stimulator of pancreatic enzyme discharge. Our data also show that the stimulatory effect of PHA on pancreatic enzyme secretion can be blocked by urethane, an anaesthetic that is known to turn off the negative pancreatic feedback control of pancreatic function in rats.     

Inhibition of gastric acid secretion by peptide YY is independent of gastric somatostatin release in the rat

The purpose of this study was to determine whether the inhibitory action of peptide YY (PYY) on gastric acid secretion is attributable to the release of gastric somatostatin in rats. Two groups of rats (six rats/group) were anesthetized with urethane and prepared with gastric fistulas and jugular catheters. Pentagastrin (18 micrograms/kg-h) was given intravenously for 150 min to stimulate gastric acid secretion. Intravenous PYY (130 micrograms/kg-h) inhibited pentagastrin-stimulated gastric acid secretion significantly (P less than 0.05). Administration of iv PYY resulted in a 41% reduction (P less than 0.05) in pentagastrin-stimulated gastric acid secretion. In another group of anesthetized rats, administration of PYY (10(-7), 10(-8) M) failed to stimulate a release of somatostatin from the isolated-perfused rat stomach. Our findings indicate that PYY can inhibit gastric acid secretion independently of release of gastric somatostatin in the rat.     

Central noradrenergic inhibition of gastric mucosal blood flow and acid secretion in rats

To investigate the role of central noradrenaline (NA) in gastric functions, changes in mucosal blood flow (MBF) and acid secretion following electrical stimulation of the lateral hypothalamic area (LHA) and the effects of NA on these parameters were examined in rats anesthetized with urethane. NA 10 μg/animal injected into the lateral ventricle decreased the basal value of both the gastric MBF and acid output, while the same dose of acetycholine or dopamine was without effect. Repetitive electrical stimulation of LHA at 10 cycles/sec, 0.5 mA, 2 msec for 10 min elicited a significant, reproducible increase in both gastric MBF and acid output. NA 10 μg/animal injected into the lateral ventricle completely blocked these increases induced by the electrical stimulation. These data suggest that a central noradrenergic inhibitory mechanism is involved in regulation of the gastric MBF and acid secretion.     

Inhibition of gastric acid secretion in dogs by neurotensin

Neurotensin is a tridacapeptide which has been isolated from bovine hypothalamus. The action of synthetic neurotensin was studied on gastric acid secretion in dogs provided with gastric pouches. Intravenously infused neurotensin, 50 ng × kg^?1 × min^?1, was found to produce a considerable inhibition of pentagastrin stimulated gastric acid secretion. On the other hand, there was no sign of inhibition of histamine induced gastric acid secretion. The experiments show that neurotensin, isolated from the central nervous system is a potent gastric secretory inhibitor and that it has a selective action in inhibiting gastric acid responses to pentagastrin but not to histamine.     

Effect of galanin on gastrin and somatostatin release from the rat stomach

Galanin has been shown to be present in the gastrointestinal tract, pancreas and CNS. In the rat stomach, immunohistochemical studies have revealed the presence of galanin in the intrinsic nervous system suggesting a function as putative neurotransmitter or neuromodulator which could affect neighbouring exo- or endocrine cells. Therefore this study was performed to determine the effect of galanin on the secretion of gastrin and somatostatin-like immunoreactivity (SLI) from the isolated perfused rat stomach. The stomach was perfused via the celiac artery and the venous effluent was collected from the portal vein. The luminal content was kept at pH 2 or 7 Galanin at a concentration of 10(-10), 10(-9) and 10(-8) M inhibited basal gastrin release by 60-70% (60-100 pg/min; p less than 0.05) at luminal pH 7. At luminal pH 2 higher concentrations of galanin (10(-9) and 10(-8) M) decreased basal gastrin secretion by 60-70% (60-100 pg/min; p less than 0.05). This inhibitory effect was also present during infusion of neuromedin-C, a mammalian bombesin-like peptide that stimulates gastrin release. SLI secretion remained unchanged during galanin administration. The inhibitory action of galanin on gastrin secretion was also present during the infusion of tetrodotoxin suggesting that this effect is not mediated via neural pathways. The present data demonstrate that galanin is an inhibitor of basal and stimulated gastrin secretion and has to be considered as an inhibitory neurotransmitter which could participate in the regulation of gastric G-cell function.     

The effect of neurotensin and secretin on gastric acid secretion and mucosal blood flow in man

Neurotensin stimulates pancreatic secretion directly and by potentiating the effect of secretin. Neurotensin also inhibits gastric secretion. Secretin inhibits gastric secretion as well, but whether it also interacts with neurotensin is not known. Secretin is known to inhibit gastric mucosal blood flow (GMBF). The effect of neurotensin on GMBF is not known. Acid secretion (triple lumen perfused orogastric tube) and GMBF ([14C]aminopyrine clearance) were therefore measured in 6 subjects during neurotensin, secretin and neurotensin plus secretin infusions. Neurotensin plus secretin reduced acid secretion by a median 130 (range 34-394) mumol/min which was significantly greater than either neurotensin at 36 (7-67) mumol/min or secretin 54 (20-347) mumol/min alone (P less than 0.05). This effect appeared independent of GMBF. Neurotensin plus secretin reduced GMBF by 14 (12-27) ml/min but not significantly more than neurotensin at 11 (3-20) ml/min or secretin 18 (2-27) ml/min alone. Further, there was no correlation between changes in acid output and GMBF during infusion of the peptides. We conclude that the inhibitory effects of neurotensin and secretin on gastric secretion are at least additive and together they may function as an 'enterogastrone'.     

Effect of neurotensin and neurotensin fragments on gastric acid secretion in man

The effect of intravenous infusion of neurotensin (NT) and NT-fragments on pentagastrin stimulated gastric acid secretion was investigated in healthy subjects. Neurotensin was infused in three doses (72, 144 and 288 pmol/kg per h). An N-terminal fragment (NT 1-8), a C-terminal fragment (NT 8-13) and an NT-analogue, substituted at the C-terminal tyrosine residue (Phe11-NT) were infused in two doses (72 and 144 pmol/kg per h). Concentrations of the infused peptides were measured in peripheral venous blood by radioimmunoassay. Plasma levels of NT 1-13, NT 1-8 and Phe11-NT increased in a dose-dependent manner; NT 1-13 to 50 (34-69), 78 (54-113) and 143 (112-242) pmol/l (medians and range) at 72, 144 and 288 pmol/kg per h, NT 1-8 to 405 (340-465) and 1215 (915-1300) pmol/l, and Phe11-NT to 200 (110-245) and 390 (250-410) pmol/l at 72 and 144 pmol/kg per h, respectively. Increases in plasma levels of NT 8-13 could not be detected during the infusion, suggesting that the fragment is rapidly metabolized in man. Neurotensin 1-13 inhibited gastric acid secretion in a dose-dependent manner and the decrease in gastric acid secretion was linearly related to plasma levels of NT 1-13. Neurotensin 1-8 and NT 8-13 inhibited gastric acid secretion only at 144 pmol/kg per h, while the analogue Phe11-NT had no effect. The results showed that the inhibition of gastric acid secretion produced by NT was dose-dependent and linearly related to circulating levels of NT, and that under physiological conditions this effect presumably is elicited by the C-terminal part of the peptide.