Effects of diazepam and Ro 15-1788 on duodenal bicarbonate secretion in the rat

Bicarbonate secretion by duodenal mucosa just distal to the Brunner's glands area and devoid of pancreatic secretions was titrated in situ in anesthetized rats. Intravenous injection of diazepam (0.1 and 0.5 mg/kg) significantly increased the secretion; this stimulation was abolished by proximal bilateral vagotomy. Ro 15-1788, a benzodiazepine antagonist that also has well-known intrinsic activity, caused similar stimulation of the secretion when administered IV (0.01 and 0.1 mg/kg). Intracerebroventricular infusion of Ro 15-1788 (10 micrograms/h) resulted in a greater increase in secretion; again, this stimulation was prevented by vagotomy. Adrenoceptor blockade by phentolamine increased basal alkaline secretion but did not affect the stimulation by diazepam. The tricyclic antidepressant trimipramine (2.5 mg/kg IV) did not affect the duodenal bicarbonate secretion. For comparison, effects of diazepam and Ro 15-1788 (10(-6)-10(-4) mol/L) were also tested in isolated bullfrog duodenal mucosa. Neither drug effected the alkaline secretion in vitro. The combined results strongly suggest that benzodiazepines, as previously shown for certain brain peptides, influence the central nervous control of duodenal mucosal alkaline secretion and that their stimulation of secretion is vagally mediated. This action benzodiazepines might be used in modulating mucosal protection against acid.     

Stimulation of duodenal bicarbonate secretion in conscious rats by cerebral somatostatin-28. Role of neurohumoral pathways

The central nervous system effects of somatostatin-28 on proximal duodenal bicarbonate secretion were studied in freely moving rats. Cerebroventricular administration of somatostatin-28 (0.2-2.0 nmol) significantly stimulated duodenal bicarbonate secretion in a dose-dependent fashion. Somatostatin-28 was approximately twice as effective as somatostatin-14. Intravenous administration of somatostatin-28 or somatostatin-14 did not significantly alter the bicarbonate response. Ganglionic blockade with chlorisondamine and truncal vagotomy abolished the stimulatory effect of somatostatin-28 while bretylium, naloxone, indomethacin, and adrenalectomy did not. Furthermore, atropine methylnitrate significantly attenuated and the vasoactive intestinal peptide antagonist 4Cl-D-Phe6, Leu17-vasoactive intestinal peptide abolished the bicarbonate response produced by cerebroventricular somatostatin-28. In contrast, hypophysectomy and pretreatment with the vasopressin V1-receptor antagonist [1-deaminopenicillamine, 2-(0-methyl)Tyr, 8-Arg]-vasopressin significantly enhanced the bicarbonate response produced by cerebroventricular somatostatin-28. These findings indicate that somatostatin-28 acts within the central nervous system to stimulate duodenal bicarbonate secretion in freely moving rats via vagal efferents by release of vasoactive intestinal peptide and, in part, by a muscarinic pathway and not by catecholamine, opiate, or prostaglandin release.     

The role of gastrointestinal peptides on pancreatic secretion in response to different stimulants in conscious rats

Summary Effects of intragastric food, intraduodenal amino acids, and intravenously administered bombesin and gastrin-releasing peptide (GRP) were examined in conscious rats with pancreatic fistula in terms of responses of exocrine pancreatic secretion, plasma levels gastrin, and cholecystokinin (CCK). Pancreatic juice and blood samples were collected at regular intervals before and after the stimuli. Intragastric food increased pancreatic secretion and plasma levels of gastrin and CCK. Intraduodenal infusion of amino acids had no effect on pancreatic secretion and plasma levels of gastrin and CCK. Intravenous infusion of bombesin at 1 μg/kg/h induced significant increases in pancreatic volume and protein outputs, but had no effect on plasma levels of gastrin and CCK. Bombesin infusion at 10 μg/kg/h resulted in significant increases in pancreatic volume and protein outputs as well as plasma gastrin levels, but had no effect on plasma CCK levels. Intravenous infusion of GRP induced increases in pancreatic volume and protein outputs and plasma gastrin levels, but had no effect on CCK levels. Antrectomy resulted in significant decreases in basal levels of plasma gastrin. GRP-stimulated pancreatic volume and protein outputs were not significantly changed by antrectomy. In rats that underwent antrectomy, GRP infusion significantly increased pancreatic volume and protein outputs, but had no effect on plasma levels of gastrin and CCK. Food-stimulated pancreatic secretion and plasma levels of gastrointestinal peptides of rats were similar to other species, but amino acids, bombesin, or GRP may not be the stimulants for CCK release in rats. The stimuli that release CCK from duodenal mucosa probably varies among species.     

Regulation of duodenal bicarbonate secretion during stress by corticotropin-releasing factor and beta-endorphin.

Proximal duodenal mucosal bicarbonate secretion is an important factor in the pathogenesis of duodenal ulcer disease. To examine the central nervous system regulation of duodenal bicarbonate secretion, an animal model was developed that allowed cerebroventricular and intravenous injections as well as collection of duodenal perfusates in awake, freely moving rats. The hypothalamic peptide corticotropin-releasing factor (CRF) and stress (physical restraint) significantly stimulated duodenal bicarbonate secretion. These responses were abolished by pretreatment of the animals with the CRF receptor antagonist alpha-helical CRF-(9-41), hypophysectomy, and naloxone. In contrast, blockade of autonomic efferents by surgical and pharmacological means did not prevent the stimulatory effects of stress and CRF. Intravenous, but not cerebroventricular, administration of beta-endorphin that produced plasma concentrations of beta-endorphin that were similar to those produced by exogenous CRF and stress significantly stimulated duodenal bicarbonate secretion. These results indicate that endogenous CRF released during stress and exogenously administered CRF stimulate duodenal bicarbonate secretion by release of beta-endorphin from the pituitary, thus, demonstrating a functional hypothalamus-pituitary-gut axis.     

The effect of vasoactive intestinal peptide, secretin, and glucagon on human duodenal bicarbonate secretion

Duodenal luminal acidification increases duodenal mucosal bicarbonate production and also releases both secretin and vasoactive intestinal peptide (VIP). The effect of these two structurally similar peptides on human duodenal bicarbonate production has not been examined in humans. Our purpose was therefore to assess the effect of VIP and secretin and also glucagon, a homologous hormone, on human duodenal bicarbonate secretion. A 4-cm portion of either proximal or distal duodenum was isolated and perfused with iso-osmolar NaCl. Pure porcine VIP (200 and 400 pmol/kg-h intravenously) significantly increased proximal duodenal bicarbonate secretion. Although secretin (0.01 to 0.18 CU/kg-h intravenously) markedly increased pancreatic bicarbonate secretion, it failed to alter duodenal mucosal bicarbonate output in either the proximal or the distal duodenum. Glucagon (1 to 8 micrograms/kg-h intravenously) did not affect proximal duodenal mucosal bicarbonate output. It is concluded that VIP, but neither secretin nor glucagon, significantly stimulates human duodenal mucosal bicarbonate secretion.     

Intracerebroventricular neuropeptide Y stimulates bile secretion via a vagal mechanism.

The effect of intracerebroventricular injection of neuropeptide Y on biliary secretion was studied in conscious dogs, prepared with gastric and duodenal fistulas and cerebroventricular guides. Bile secretion was increased in a dose-dependent fashion by intracerebroventricular neuropeptide Y. The peak increase was seen after 500 pM/kg of neuropeptide Y which resulted in a 30 x 2% increase in bile flow over the period 30-150 minutes after injection. (Control: 23 x 2 (1 x 2) ml/2 hours; neuropeptide Y 500 pM/kg: 30 x 5 (1 x 1) ml/2 hours). Biliary lipid composition was not altered significantly but bicarbonate output was increased at all doses tested. Intravenous infusion of neuropeptide Y (1000 pM) for 1 hour had no significant effect. Intracerebroventricular neuropeptide Y (1000 pM/250-300 mg body weight) also increased bile flow in urethane-anaesthetised rats. This effect was abolished by cervical vagotomy. The demonstration of a central stimulation of alkaline bile flow suggests that bile secretion may be subject to central modulation.     

Central nervous system actions of calcitonin gene-related peptide on gastric acid secretion in the rat

Calcitonin gene-related peptide (CGRP) and its messenger ribonucleic acid have been identified in brain regions that participate in the central nervous system regulation of gastrointestinal functions. The purpose of this study was to determine the central nervous system effect of CGRP on gastric acid secretion and to delineate the mechanism(s) of its action. Calcitonin gene-related peptide (1 pmol-1 nmol) injected intracerebroventricularly inhibited gastric acid secretion in awake, freely moving, pylorus-ligated rats and the secretory response after intracerebroventricularly administered thyrotropin-releasing hormone. Calcitonin gene-related peptide (rat) and calcitonin (salmon) inhibited gastric secretion similarly. Calcitonin gene-related peptide given intracerebroventricularly inhibited gastric acid secretion stimulated by pentagastrin, histamine, or bethanecol for 2 h in anesthetized rats. Adrenalectomy or noradrenergic blockade with bretylium tosylate did not affect the gastric inhibitory action of CGRP. After subdiaphragmatic truncal vagotomy, CGRP did not exhibit the inhibitory effect on gastric acid secretion stimulated by pentagastrin. These studies indicate that CGRP injected intracerebroventricularly is a potent inhibitor of gastric acid secretion in the rat. Calcitonin gene-related peptide decreases gastric secretion stimulated centrally by thyrotropin-releasing hormone and peripherally by pentagastrin, histamine, or bethanecol. Inhibition of gastric acid secretion by CGRP is not mediated by the sympathetic nervous system but may depend on intact vagus nerves.     

Intrathecal injection of bombesin inhibits gastric acid secretion in the rat

Bombesin (100-500 ng) injected intrathecally (T9-10) inhibited gastric acid secretion stimulated by pentagastrin and the GABAB agonist baclofen in urethane-anesthetized rats and basal gastric acid secretion in conscious, pylorus-ligated rats. Peptide action was dose-related, occurred within 30 min, and lasted for greater than 1 h. Bombesin-induced inhibition of pentagastrin-stimulated gastric acid secretion was not altered by cervical cord transection. Intravenous infusion of the monoclonal bombesin antibody 2A11 abolished intravenous bombesin (10 micrograms/kg.h)-induced 33% inhibition of gastric response to pentagastrin but did not alter intrathecal bombesin (200 ng)-induced 38% inhibition of gastric response to pentagastrin. The inhibitory effect of bombesin (200 ng) on pentagastrin-stimulated gastric secretion was reversed by bilateral adrenalectomy or removal of celiac and mesenteric ganglia. Intrathecal injections of rat calcitonin gene-related peptide, neuromedin B, neuromedin U, and the stable substance P analogue (pGlu5, MePhe8, MeGly9)-substance P(5-11) did not alter pentagastrin-stimulated gastric acid secretion. These results demonstrate that bombesin injected into the subarachnoid space of the spinal cord inhibits vagally stimulated and pentagastrin-stimulated gastric secretion in rats. Bombesin action is peptide specific, exerted at a spinal site, and expressed through the sympathetic nervous system.     

Central nervous alpha1-adrenoceptor stimulation induces duodenal luminal release of melatonin

Intracerebroventricular (i.c.v.) infusion of the alpha1-adrenoceptor agonist phenylephrine elicits vagal and sympathetic neural stimulation of the bicarbonate secretion by the duodenal mucosa. Melatonin originating from mucosal enterochromaffin cells (EC cells) has been proposed to mediate this centrally elicited stimulation. However, the release of intestinal melatonin has not been studied. Rats were anesthetized with thiobarbiturate, a 12-mm segment of duodenum with intact blood supply was cannulated in situ and bicarbonate secretion titrated by pH-stat. The mean arterial blood pressure was continuously recorded. Melatonin in the duodenal luminal perfusate was determined by high-performance liquid chromatography with electrochemical detection. Intracerebroventricular infusion of phenylephrine (12.2 microM/kg/hr) induced more than 10-fold increase in release of melatonin into the duodenal lumen and an increase in HCO secretion from 7.6 +/- 0.5 to 18.6 +/- 2.1 microEq/cm/hr. The melatonin receptor (MT2 > MT1) antagonist luzindole (600 nM/kg, i.v.) almost abolished the marked rise in bicarbonate secretion induced by i.c.v. phenylephrine but, in contrast, did not affect the release of melatonin. These results strongly suggest that release of melatonin from the mucosa mediates the duodenal secretory response to centrally elicited neural stimulation.     

Cerebroventricular bombesin inhibits gastric acid secretion in dogs

Bolus injections of bombesin into a lateral cerebral ventricle of conscious beagle dogs inhibited pentagastrin-stimulated gastric acid secretion from both the innervated stomach (gastric fistula) and the vagally denervated Heidenhain pouch in a dose dependent manner. Bombesin (300 ng/kg), injected into the lateral ventricle, inhibited acid secretion from the gastric fistula and Heidenhain pouch by 66% +/- 5% and 93% +/- 4%, respectively. Central administration of bombesin also suppressed acid secretion in response to a meal by 52% +/- 15%; postprandial gastrin response was not affected. By contrast, intravenous infusion of bombesin stimulated both gastrin release and acid secretion without affecting the acid response to a submaximal dose of pentagastrin. The opposing effects of central and peripheral bombesin on acid secretion indicate that the gastric response to intracerebrally administered bombesin is mediated by the central nervous system. Furthermore, the inhibitory action of bombesin injected into the lateral cerebral ventricle is independent of the vagus and is not mediated by the inhibition of gastrin release. These observations demonstrate that bombesin-like peptides may act centrally to alter gastric secretion.     

Thyrotropin-releasing hormone inhibits pancreatic enzyme secretion in humans

Recent studies have shown that thyrotropin-releasing hormone is present in gastrointestinal tissues and has effects on gastrointestinal motility and secretion. In the present study, we have investigated in healthy subjects the effects of various doses of thyrotropin-releasing hormone on secretin-cholecystokinin-stimulated pancreatic secretion. Intravenous infusion of thyrotropin-releasing hormone at doses of 4, 20, and 100 microgram/30 min, administered during a constant pancreatic stimulation with secretin (0.5 Clinical Units/kg/h) and cholecystokinin (0.5 Ivy dog units/kg/h), produced a significant decrease in lipase and chymotrypsin secretion without affecting volume and bicarbonate secretion. The decrease appeared immediately with the lowest dose of TRH employed, and was progressively more marked with increasing doses of the hormone. Compared with the control experiments, the maximal inhibition of lipase output reached -17.6%, -37.2%, and -43%, and the maximal inhibition of chymotrypsin output -18.2%, -39.3%, and -44.9%, for the three doses of thyrotropin-releasing hormone employed, respectively. It is concluded that TRH has a marked inhibitory effect on the enzymatic component of the pancreatic secretion stimulated by submaximal doses of secretin and cholecystokinin. The physiologic importance of this effect remains to be defined.     

Calcitonin gene-related peptide: potent peripheral inhibitor of gastric acid secretion in rats and dogs

Calcitonin gene-related peptide is a 37-residue peptide recently characterized in central and peripheral nervous system. The pharmacologic or physiologic importance of this peptide is not known. We studied the effect of calcitonin gene-related peptide on exogenously stimulated gastric acid secretion (pentagastrin, histamine, bethanechol, and intracisternal thyrotropin-releasing hormone) in the urethane-anesthetized rat. Calcitonin gene-related peptide (2.6 nmol/kg X h) caused a 63%-78% inhibition of gastric acid secretion with all secretagogues tested. The inhibition of gastric acid response to pentagastrin was dose-dependent (2.6-2630 pmol/kg X h), rapid in onset, quickly reversible upon cessation of calcitonin gene-related peptide infusion, and not modified by acute vagotomy or indomethacin pretreatment. In conscious dogs, gastric fistula acid response to pentagastrin was inhibited in a dose-dependent manner by calcitonin gene-related peptide (2.6-260 pmol/kg X h). The acid response of the Heidenhain pouch to pentagastrin was also inhibited by calcitonin gene-related peptide (260 pmol/kg X h). These results show that calcitonin gene-related peptide is a potent inhibitor of gastric acid secretion in the rat as well as in the dog. Its inhibitory action could be demonstrated against various stimuli and appears to be independent of prostaglandin or vagal pathways.     

Divergent effects of bombesin and bethanechol on stimulated gastric secretion in duodenal ulcer and in normal men

To further investigate differences in the responses of normals and patients with duodenal ulcer with respect to gastrin release and acid and pepsin secretion, we infused bombesin (1 microgram/kg X h) or bethanechol (40 micrograms/kg X h) during the middle hour of a 3-h infusion of pentagastrin and compared the results with a pentagastrin infusion without added drug. Pentagastrin dosage (0.1 microgram/kg X h) was set to give about half-maximal response, to detect either inhibition or further stimulation of gastric secretion, whereas the dose of bombesin was chosen to give maximal gastrin but less than maximal acid secretion. Serum gastrin and somatostatin were also measured. In all subjects tested, bethanechol produced no effects on acid, gastrin, or somatostatin release but increased pepsin output. By contrast, bombesin inhibited pentagastrin-stimulated acid output in all 6 normal men by an average of 55%, whereas it inhibited acid output in only 2 of the 9 men with duodenal ulcer. Serum gastrin increases after bombesin in duodenal ulcer were three to four times greater than in normals. Although bombesin stimulates acid only by releasing gastrin, we postulate that bombesin may also simultaneously limit acid and pepsin secretion and speculate that this effect could be mediated by bombesin-induced somatostatin release. The cause for differences between duodenal ulcer and normal remain speculative.     

Brain regulation of gastric secretion: influence of neuropeptides.

Several neuropeptides injected intracisternally were assessed for their effects on gastric secretion in rats. Bombesin (1 microgram) completely suppressed gastric acid secretion, produced the volume of gastric secretion, and partially blocked insulin- or 2-deoxy-D-glucose-induced stimulation of gastric acid output. The inhibitory effect of this peptide is dose-dependent, long-acting, reversible, and specific. Bombesin response appears to be central nervous system-mediated; its expression is not dependent on the vagus nerve or the adrenal glands, and does not rely on a decrease in gastrin secretion. Among seven other peptides tested, only beta-endorphin and a potent gonadotropin releasing-factor (gonadoliberin) agonist significantly reduced gastric acid secretion, with an activity ca. 100 times less than that of bombesin. The presence of bombesin-like material in rat brain and the high potency of bombesin to inhibit gastric secretion suggest that this peptide may be of physiologic significance as a chemical messenger involved in brain modulation of gastric secretion.     

Effect of Stimulation of Mucosal HCO‐ Secretion on Acid-Induced Injury to Porcine Duodenal Mucosa

The effect of stimulation of duodenal mucosal bicarbonate secretion with vasoactive intestinal peptide (VIP) on acid-induced damage to the duodenal mucosa was studied in anaesthetized pigs in which bile and pancreatic juice were diverted from the duodenum. Mucosal damage was quantitatively assessed histologically, and mucosal blood flow was determined by means of radioactively labelled microspheres. Compared with placebo, intravenous infusion of VIP (500 pmol/kg/h) significantly stimulated duodenal mucosal bicarbonate secretion (47 ± 13 versus 249 ± 53 μmol/h) without concomitant changes in mucosal blood flow (51.5 ± 7.8 versus 48.5 ± 9.1 ml/min/100g) or arterial bicarbonate concentration (24.2 ± 1.1 versus 23.4 ± 0.9 mM). The same dose of VIP increased the acid disappearance rate in the duodenum (2.2 ±0.14 versus 3.3 ± 0.09 mmol/h) and reduced the extent of damage to the duodenal surface (16 ± 2% versus 7 ± 2%) during duodenal infusion of 0.03 M HC1 but not 0.1 M HCI. We conclude that the protection offered by VIP against the small dose of acid is most likely secondary to the effect of VIP on mucosal bicarbonate secretion. Thus, this study suggests that duodenal mucosal bicarbonate secretion, independent of mucosal blood flow, is an integral factor in duodenal mucosal defence.     

Effect of the cholecystokinin-receptor antagonist lorglumide on pancreatic enzyme secretion stimulated by bombesin, food, and caerulein, giving similar plasma cholecystokinin concentrations in the dog.

This study was undertaken to determine the role of cholecystokinin in pancreatic enzyme secretion stimulated by bombesin and a meal by (a) comparing the pancreatic enzyme output during bombesin infusion and after a meal to output during caerulein infusion and (b) comparing the inhibitory effect of the cholecystokinin-receptor antagonist lorglumide (CR-1409) on enzyme output in response to bombesin and food with the response to caerulein. Bombesin (90 pmol/kg per h) and caerulein (30 pmol/kg per h) were infused into seven dogs in doses giving similar plasma cholecystokinin peak increments as a meal (mean (SEM) 6.8 (0.8), 6.3 (1.2), and 5.7 (0.8) pM, respectively), together with either saline or 2 mg/kg per h of lorglumide. A background infusion of synthetic secretin 20.5 pmol/kg per h was given in each experiment. In addition, gastric acid secretion was determined in the experiments with bombesin and caerulein infusion. Pancreatic protein responses to bombesin (1231 (247) mg/h) and food (1430 (220) mg/h) were similar to the responses to caerulein (1249 (201) mg/h). Lorglumide inhibited pancreatic protein output during stimulation with bombesin by 60%, after the meal by 45%, and during caerulein infusion by 68%. Pancreatic bicarbonate output by bombesin, caerulein, and food was inhibited by lorglumide by 28%, 40%, and 38%, respectively. In contrast, lorglumide significantly increased gastric acid secretion from 1.12 to 7.98 mmol/h during bombesin infusion and from 0.52 to 7.62 mmol/h during caerulein infusion. In conclusion, cholecystokinin plays an important part in the stimulation of pancreatic enzyme secretion by bombesin and a meal in conscious dogs and it is involved in the regulation of gastric acid during stimulation by infusions of caerulein and bombesin.     

Stimulation of amphibian gastroduodenal bicarbonate secretion by sucralfate and aluminium: role of local prostaglandin metabolism.

The present studies were designed to explore the possible mode of protective and ulcer healing actions of sucralfate by examining its effect on gastroduodenal bicarbonate secretion by isolated amphibian mucosa. Luminal sucralfate (0.5 g/l) significantly increased bicarbonate secretion by fundic and antral mucosa without influencing transmucosal potential difference. Significant stimulation of duodenal bicarbonate secretion occurred only at 1.0 g/l without change in potential difference. Aluminium, a component of sucralfate, produced similar increases in bicarbonate secretion, while the sucrose and sulphate components were without effect. Pretreatment of mucosae with the cyclooxygenase inhibitor, indomethacin (10 5M) did not abolish the secretory response to sucralfate or aluminium. The results suggest that stimulation of gastroduodenal bicarbonate secretion, possibly by the aluminium moiety of sucralfate, may play a role in its protective and ulcer healing actions.     

Central nervous system action of thyrotropin-releasing hormone to increase gastric mucosal blood flow in the rat

The central nervous system effects of thyrotropin-releasing hormone (TRH) on gastric acid secretion and mucosal blood flow were studied in rats. Corpus mucosal blood flow was measured by the hydrogen gas clearance technique and acid output by a continuous gastric perfusion method in fasted, urethane-anesthetized rats. Thyrotropin-releasing hormone (1 or 5 micrograms) injected into the cerebral lateral ventricle induced concomitant increases in gastric acid secretion and mucosal blood flow. Intravenous infusion of step doses of TRH (60 and 180 micrograms/kg.h) had no effect on these parameters. Bilateral vagotomy and atropine (0.15 mg/kg) completely blocked the effects of intracerebroventricular injection of TRH (5 micrograms) on gastric acid secretion and mucosal blood flow. In contrast, intravenous omeprazole (20 mumol/kg) completely inhibited the increase in gastric acid secretion but not the increase in mucosal blood flow elicited by intracerebroventricular administration of TRH (5 micrograms). These results demonstrate that TRH acts in the brain to stimulate gastric acid secretion and mucosal blood flow through vagal dependent pathways and peripheral muscarinic receptors. Part of the effect of central TRH on gastric mucosal blood flow is not secondary to the stimulation of acid secretion and appears to represent a direct cholinergic vasodilatory response.     

Effects of gamma-aminobutyric acid and peripheral benzodiazepine ligands on duodenal bicarbonate secretion

BACKGROUND: The effects of gamma-aminobutyric (GABA(A))-receptor ligands and peripheral-type benzodiazepine (BZ) ligands on duodenal mucosal bicarbonate secretion (DBS) were studied in thiobarbiturate-anesthetized rats. METHODS: A segment of proximal duodenum was perfused, and bicarbonate secretion was continuously titrated by pH-stat. In some experiments the vagus nerves were dissected free and cut at the neck level. RESULTS: Luminal GABA (10(-8) to 10(-6) M) increased (P < 0.01) DBS dose-dependently, and the GABA(A) antagonist (+)-bicuculline (0.1-2.5 mg/kg intravenously) caused a similar increase (P < 0.01) in DBS. Vagotomy abolished the latter response, suggesting a centrally elicited nervous action of bicuculline mediated by the vagal nerves. This was supported by the absence of an effect of bicuculline administered intra-arterially close to the duodenum. The GABA(A) agonist muscimol had no effect on DBS when administered intravenously (0.01-0.25 mg/kg) or into a lateral brain ventricle (2 microg/kg/h) but counteracted any stimulation by subsequent intravenous bicuculline. The 'peripheral-type' BZ agonist 4'-chlorodiazepam increased DBS when infused close intra-arterially but had no effect when administered intravenously. CONCLUSIONS: Inhibition of GABA(A) receptors related to cholinergic excitatory pathways in the central nervous system stimulates duodenal mucosal bicarbonate secretion and may increase the local mucosal defense. The stimulation by luminal GABA may reflect modulation of the local mucosal control of duodenal bicarbonate secretion.     

Morphine Inhibits Secretion of Bicarbonate from the Human Duodenal Mucosa: Possible Role of Endogenous Opioids in the Regulation of Human Duodenal Mucosal Bicarbonate Secretion

Mucus and bicarbonate secreted from the epithelium are thought to be important for the protection of the duodenal mucosa against acid and pepsin, but so far little is known about the regulation of human duodenal mucosal bicarbonate secretion. After isolating a segment of the proximal human duodenum from gastric and pan-creaticobiliary secretion we quantified the secretion of bicarbonate from the human duodenal mucosa. The method was evaluated by measurements of basal and prosta-glandin E¹ analogue-stimulated bicarbonate secretion. The duodenal mucosal bicarbonate secretion was inhibited 70% after intravenous infusion of morphine in a dose of 73.6 μg/kg/h and increased after intravenous administration of naloxone. Thus, the inhibition is most likely mediated by μ-receptors, and the results suggest a role of endogenous opioids in the regulation of the secretion of bicarbonate from the human duodenal mucosa.