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The influence of neurotransmitters on gastrointestinal motility is different in different segments of the gastrointestinal tract. To clarify the regulation of duodenal motility, the aim of the present study was to investigate the effects of alpha-adrenoceptor agonism and blockade and of galanin on duodenal motility. The study was undertaken in the isolated perfused porcine pancreatico-duodenal block. The agents under investigation were administered arterially. Duodenal motility was measured by means of a low-compliance perfusion system using an intraluminal catheter. In addition the concentration of galanin was measured in the portal effluent. We found that spontaneous motility was abolished by noradrenaline by an effect that was counteracted by the alpha 2-adrenoceptor antagonist idazoxan. In contrast, the selective alpha 1-adrenoceptor antagonist prazosin did not influence the effect of noradrenaline. Galanin, like noradrenaline, abolished duodenal motility. Furthermore, the concentration of galanin in the portal effluent was decreased by noradrenaline by an alpha 2-adrenoceptor mediated mechanism. We conclude that alpha 2-adrenoceptor activation and galanin inhibit duodenal motility and that the release of galanin from the pancreatico-duodenal preparation is reduced by alpha 2-adrenoceptors.

The neuropeptide galanin is known to inhibit insulin secretion in a variety of species. However, controversies exist regarding its action on insulin secretion in the perfused pig pancreas, since both inhibitory and stimulatory effects have been described. We therefore perfused the isolated porcine pancreatico-duodenal block with galanin (100 nmol/l) in the presence of 5 or 15 mmol/l glucose or with 5 mmol/l glucose and 10 mumol/l tolbutamide. We found that at this dose level, galanin did not affect insulin secretion stimulated by glucose alone. In contrast, galanin clearly suppressed tolbutamide-stimulated insulin secretion. Hence, we conclude that galanin has a weak influence on insulin secretion in the pig pancreas, being unable to inhibit glucose-stimulated insulin secretion at the dose level of 100 nmol/l. However, when active, galanin clearly inhibits insulin secretion also in the pig pancreas.

This study was designed to determine the occurrence and topographical distribution of galanin-like immunoreactivity (GAL-LI) in the porcine gallbladder and sphincter of Oddi and to investigate the pharmacologic effect of GAL on gallbladder and sphincter of Oddi motility. By radioimmunoassay the concentration of GAL-LI in the gallbladder was 2.75 +/- 0.23, 9.73 +/- 1.33 in the common bile duct and 5.10 +/- 0.37 in the sphincter of Oddi (pmol/g +/- SE). By immunohistochemistry GAL-LI was found exclusively in ganglionic cells and in nerve fibers among the smooth muscle bundles. Gallbladder and sphincter of Oddi pressures were recorded before and during 5-minute local intraarterial infusion of 4, 8, 19, 39, 78 and 194 ng GAL - Kg-1 - min-1 in 12 anaesthetized pigs. GAL in doses greater than or equal to 39 ng.kg-1.min-1 significantly reduced sphincter of Oddi phasic wave frequency (4.8 +/- 0.4 vs. 2.1 +/- 0.5; p = 0.004) and sphincter of Oddi motility index (70.2 +/- 6.02 vs. 27.7 +/- 8.3; p = 0.002) but did not affect gallbladder pressure. We conclude that the distribution of GAL-LI in the sphincter of Oddi and the effect that a pharmacologic dose of GAL has on sphincter of Oddi motor activity, suggests that GAL may be involved in the physiologic control of bile flow in the pig.

The effect of vasoactive intestinal polypeptide (VIP), enkephalin, neuropeptide Y, gastrin, cholecystokinin, neurotensin, somatostatin, and thyrotropin-releasing hormone on the lower esophageal sphincter pressure (LESP) was studied in anesthetized pigs. The peptides were infused into the arterial supply of the lower esophageal sphincter in graded doses during electrical stimulation of the vagal nerve (9 V, 10 Hz, 3 msec). The vagally stimulated LESP was inhibited by VIP (0-40 pmol/kg/min) and enkephalin (0-200 pmol/kg/min) in a dose-dependent manner. The other peptides had no effect on the stimulated LESP regardless of the dose tested. The results suggest that VIP and enkephalin may influence the stimulated LESP under normal conditions and that the other peptides tested did not affect the physiological regulation of the LESP. Furthermore, the vagally stimulated LESP was inhibited by atropine (250 micrograms/kg intravenously) but not by guanethidine (1 mg/kg intravenously).

The 27-amino acid peptide gastrin releasing peptide (GRP-(1-27] was infused at 4 dose levels (0.01, 0.1, 1.0, and 10 nM) into the arterial line of the isolated perfused porcine pancreas. Infusions were performed at 3 different perfusate glucose levels (3.5, 5.0, and 8.0 mM) and at two levels of amino acids (5 and 15 mM). GRP-(1-27) stimulated insulin and pancreatic polypeptide secretion and inhibited somatostatin secretion in a dose-dependent manner. Glucagon secretion was unaffected by infusion of GRP under all circumstances. The effect of GRP-(1-27) on insulin secretion was enhanced with increasing perfusate glucose levels, whereas the effects upon somatostatin and pancreatic polypeptide secretion were independent of perfusate glucose levels. The responses to GRP were unaffected by elevation of the concentration of amino acids in the perfusate. The effects of GRP were unaffected by atropine at 10(-6) M. The localization of GRP within the porcine pancreas, its release during electrical stimulation of the vagus nerve, and its potent effects upon pancreatic endocrine secretion make it conceivable that the peptide participates in parasympathetic regulation of pancreatic endocrine secretion.

The effect of gastrin-releasing peptide (GRP) on pancreatic exocrine secretion was studied by infusing it at four dose levels (0.01, 0.1, 1.0, and 10 nmol/l) into the arterial line of the isolated perfused porcine pancreas. At 1.0 nmol/l GRP stimulated protein (37-fold), fluid (13-fold), and bicarbonate secretion (12-fold). Atropine at 1 mumol/l diminished the protein secretion in response to infusion of GRP at a dose of 1 nmol/l to 45% of control. Fluid and bicarbonate responses were not affected by atropine treatment. Electrical stimulation of the vagus nerves resulted in an increase in pancreatic output of GRP and a concomitant stimulation of exocrine secretion. Infusions of acetylcholine, carbachol, pilocarpine, or dimethylphenylpiperazinium had no effect on the output of GRP, although hexamethonium abolished the response to vagal stimulation. It is concluded that GRP in conjunction with acetylcholine is likely to play a prominent part in parasympathetic regulation of pancreatic exocrine secretion.

THE EFFECT OF EFFERENT, PARASYMPATHETIC STIMULATION UPON PANCREATIC POLYPEPTIDE (PP) SECRETION WAS STUDIED IN THREE WAYS: (a) Plasma PP concentrations increased in response to insulin-induced hypoglycemia in both normal subjects, from 11 pM (9.5-12.5) to 136 pM (118-147), n = 8 (median and interquartile range) and in duodenal ulcer patients, from 33 pM (21-52) to 213 pM (157-233), n = 7. The PP response to hypoglycemia was diminished by atropine in normal subjects (P < 0.005) and completely abolished by vagotomy in the duodenal ulcer patients. (b) Electrical stimulation, 8 Hz, of the vagal nerves in anesthetized pigs induced an increase in portal PP concentrations within 30 s from 32 pM (28-39) to 285 pM (248-294), n = 12. Minimal stimulatory frequency was 0.5 Hz and maximal stimulatory frequency 8-12 Hz. Atropine inhibited the PP response to electrical stimulation. Median inhibition with 0.5 mg of atropine/kg body wt was 74%, range 31-90%, n = 6. The response was eliminated by hexamethonium. Adrenergic alpha and beta blockade did not influence the release of PP in response to vagal stimulation. (c) Acetylcholine stimulated, in a dose-dependent manner, the secretion of PP from the isolated perfused porcine pancreas, half-maximal effective dose being 0.19 muM; maximal PP output in response to 5 min stimulation was 228 pmol, range 140-342 pmol, n = 5. Atropine completely abolished this response.The results of the present study together with the previously demonstrated poor PP response to food in vagotomized patients, indicate that vagal, cholinergic stimulation is a major regulator of PP secretion.

Studies were performed to investigate the effects of neurotransmitters and neurotransmitter candidates (substance P, VIP, somatostatin, Met-enkephalin, gastrin-17, CCK-4 and -8, neurotensin and TRH) of the newly discovered peptidergic nervous system on lower oesophageal sphincter pressure in anaesthetized pigs. All neuropeptides were infused over 2 min periods in 6 different doses, separated by resting periods of at least 1 min, directly into the arterial supply of the lower oesophageal sphincter. Substance P caused a dose-dependent increase in lower oesophageal shpincter pressure; the threshold dose was 9 pmol . kg-1 . min-1 and half maximal response occurred at 72 pmol . kg-1 . min-1. None of the other polypeptides, however, influenced the resting lower oesophageal sphincter. These studies show that substance P is a potent stimulant of smooth muscle in the lower oesophageal sphincter, suggesting that this peptide may be an important regulator of lower oesophageal sphincter pressure.

We extracted gastrin-releasing peptide (GRP) and its C-terminal decapeptide corresponding to 6.4 and 6.8 pmol/g from pig antrum mucosa. By immunohistochemistry GRP was localized to mucosal, submucosal, and myenteric nerve fibers. A few nerve cell bodies were also identified. Using isolated perfused pig antrum with intact vagal innervation, we found concomitant, atropine-resistant release of GRP and gastrin during electrical stimulation of the vagal nerves. Intra-arterial GRP at 10(-11)-10(-10) mol/l caused up to fivefold, dose-dependent increases in gastrin secretion; higher doses were less effective and completely desensitized the gastrin cells for the lower doses. After desensitization, vagal stimulation no longer produced gastrin secretion. The substance P antagonist [D-Arg, D-Pro, D-Trp, Leu]-substance P, described as also antagonizing the actions of bombesin, decreased the gastrin response to GRP and abolished the effect of vagal stimulation. The available evidence strongly suggests that GRP nerves are responsible for the stimulatory vagal effects on gastrin secretion in the pig.

Specimens from the lower esophageal sphincter (LES) region of the pig were analyzed for galanin-like immunoreactivity (GAL-LI) using radioimmunoassay and immunohistochemistry. The mean concentration of GAL-LI was 3.4 pmol/g tissue. GAL-LI nerve fibers were observed surrounding muscle bundles in the smooth circular muscle layer, and in ganglion cells of the myenteric plexus. Bolus injection of 40-200 pmol/kg of galanin directly into the arterial supply of the resting LES increased the LES pressure (LESP) dose-dependently, whereas slow infusion of 2-100 pmol galanin/kg/min had no effect on resting LESP. The vagally increased LESP was not modulated by simultaneous galanin infusion, and the concentration of galanin in the venous effluent of the LES declined insignificantly during vagal stimulation. It is concluded that galanin may be an important neuropeptide for the modulation of resting LES tone.

The concentrations of gastrin-releasing polypeptide, somatostatin (SS), and gastrin in extracts of endoscopically obtained biopsies from the fundus, antrum, and duodenum of patients with uncomplicated bile stones (controls) or duodenal ulcer disease were measured with specific radioimmunoassays. The validity of the tissue sampling was confirmed by characteristic and significant differences between gastrin concentrations at the different biopsy sites. Gastrin-releasing polypeptide levels were at their highest in the fundic and duodenal bulb compared to the antrum in controls (p less than 0.01), whereas no differences in gastrin-releasing polypeptide content of the different parts of the stomach were found in duodenal ulcer patients. Compared to controls gastrin-releasing polypeptide in duodenal ulcer patients was reduced in fundic and duodenal bulb mucosa (p less than 0.01). SS levels were highest (p less than 0.05) in the first part of duodenum in controls. Compared to controls duodenal ulcer patients had lower SS concentrations present in fundic (p less than 0.01) and highest SS concentrations present in duodenal bulb mucosa (p less than 0.01). There was no correlation between acid secretion and mucosal gastrin-releasing polypeptide or SS concentrations in any part of the stomach and duodenum.

The presence of gastrin-releasing peptide (GRP) was studied in extracts of porcine pancreata. Gel filtration and high-pressure liquid chromatographic profiles of these extracts as monitored with both C-terminally and N-terminally directed radioimmunoassays against GRP showed pancreatic GRP to consist of one main form, namely the 27-amino acid peptide originally extracted from porcine stomach, and small amounts of a C-terminal fragment identical with the C-terminal 10-amino acid peptide. Gastrin-releasing peptide-like immunoreactivity released from the isolated perfused porcine pancreas during electrical vagal stimulation was shown by gel filtration to consist of the same two forms. By use of immunocytochemical techniques employing an antiserum directed against its N terminus, GRP was localized to varicose nerve fibers in close association with the exocrine tissue of the porcine pancreas in particular. Some fibers were found penetrating into pancreatic islets also. Immunoreactive nerve cell bodies as well as fibers were found within intrapancreatic ganglia. The potency of GRP in stimulating exocrine as well as endocrine secretion from the porcine pancreas, its presence in close contact with both acini and islets, and its release during vagal stimulation indicate that GRP may have a role in the parasympathetic regulation of endocrine and exocrine secretion from the pig pancreas.