Tachykinins in regulation of gastric motility and secretion

The tachykinins constitute a family of neuropeptides with a common C-terminal amino acid sequence. The best known tachykinin is substance P. Tachykinins are found in the nerve plexuses and nerve fibers in the stomach of all species examined. The circular muscle layer is densely innervated, whereas the longitudinal layer and the mucosa are less intensively innervated. Tachykinins are also found in a significant number of afferent neurons with cell bodies in the dorsal root ganglia. Release of tachykinin can be demonstrated in response to both electrical stimulation of the vagus nerves and application of capsaicin. In the stomach all three known tachykinin receptors seem to be present. Although species variations exist, NK-2 receptors are generally present on the musculature, NK-1 receptors on both neurons and muscles, and NK-3 receptors on neurons only. Tachykinins stimulate motility in all parts of the stomach, but tachykinins also appear to inhibit motility in certain situations. Also, motility initiated centrally, mediated through the vagus nerves, is influenced by tachykinins. The precise role of tachykinin in the various motor programs in the stomach is not clear. Gastric acid secretion is influenced by tachykinins in several species. Tachykinins do not seem to act as neurotransmitters directly on parietal cells, but may have a modulatory function. The importance of tachykinins for the regulation of pepsinogen and hormone secretion from the stomach remains unclear. Received 24 August 1999; received after revision 1 December 1999; accepted 3 December 1999     

Inhibitory effect of ouabain on in vitro and in vivo gastric acid secretion in the frog and the rat

The in vitro and in vivo effects of ouabain on gastric acid secretion in the frog and the rat, the 2 species known to have different sensitivity to ouabain, were studied. It was found that ouabain was a potent inhibitor of histamine-stimulated acid secretion in the isolated frog gastric mucosa. Ouabain administered i.v. at dose levels far below the lethal range also produced a marked and significant reduction of histamine-stimulated gastric acid secretion in the anesthetized frogs and rats. It is considered that the inhibitory effect of ouabain on acid secretion could be partly related to its specific antagonizing action on the Na+ -K+ -ATPase in the gastric mucosa.     

Inhibitory effect of ouabain on in vitro and in vivo gastric acid secretion in the frog and the rat

Summary The in vitro and in vivo effects of ouabain on gastric acid secretion in the frog and the rat, the 2 species known to have different sensitivity to ouabain, were studied. It was found that ouabain was a potent inhibitor of histamine-stimulated acid secretion in the isolated frog gastric mucosa. Ouabain administered i.v. at dose levels far below the lethal range also produced a marked and significant reduction of histamine-stimulated gastric acid secretion in the anesthetized frogs and rats. It is considered that the inhibitory effect of ouabain on acid secretion could be partly related to ist specific antagonizing action on the Na⁺-K⁺-ATPase in the gastric mucosa.     

The islet-acinar axis of the pancreas: Is there a role for glucagon or a glucagon-like peptide?

Intravenous glucagon inhibits exocrine pancreatic secretion in vivo, but exogenous glucagon does not affect exocrine secretion in vitro. Recent work, however, suggested that endogenous glucagon may be involved in the regulation of exocrine secretion even in vitro. We therefore investigated the effects of exogenous and endogenous glucagon on exocrine secretion by the isolated perfused rat pancreas in the presence of 1.8 mM glucose. Exogenous glucagon did not affect CCK-stimulated amylase output. 20 mM arginine stimulated glucagon release, but did not affect basal enzyme secretion. CCK-stimulated amylase output, however, was significantly inhibited in the presence of arginine. This inhibitory effect of arginine on exocrine pancreatic secretion could be blocked by glucagon antibodies, but not by nonspecific gammaglobulins. Thus exogenous glucagon failed to affect exocrine pancreatic secretion in vitro, but endogenously released glucagon or a glucagon-like peptide inhibited amylase release in the isolated perfused pancreas. We conclude that glucagon or a glucagon-like peptide may be a mediator in the islet-acinar axis.     

Peptide YY enhances NaCl and water absorption in the rat colon in vivo.

Peptide YY (PYY) is thought to possess paracrine and endocrine functions. The highest concentrations of this peptide are in the colonic mucosa. The effect of PYY on electrolyte and water transport in the rat colon was studied in vivo. Under urethane anesthesia, rat colonic loops were perfused at a constant rate with physiological buffer solution containing phenol red as a nonabsorbable volume marker, and net movements of water, sodium, chloride and potassium in the perfused colon were determined every 10 min. Intravenous administration of PYY produced a dose-dependent increase in the net absorption of sodium chloride and water, as well as a decrease in the net secretion of potassium. PYY inhibited the reduction in net absorption of sodium chloride and water evoked by vasoactive intestinal peptide (VIP), but did not affect the VIP-evoked increase in net potassium secretion. These findings suggest that PYY acts as an enhancer of sodium chloride and water absorption and as an antagonist to VIP-induced secretion in the colon.     

Peptide YY enhances NaCl and water absorption in the rat colon in vivo

Peptide YY (PYY) is thought to possess paracrine and endocrine functions. The highest concentrations of this peptide are in the colonic mucosa. The effect of PYY on electrolyte and water transport in the rat colon was studied in vivo. Under urethane anesthesia, rat colonic loops were perfused at a constant rate with physiological buffer solution containing phenol red as a nonabsorbable volume marker, and net movements of water, sodium, chloride and potassium in the perfused colon were determined every 10 min. Intravenous administration of PYY produced a dose-dependent increase in the net absorption of sodium chloride and water, as well as a decrease in the net secretion of potassium. PYY inhibited the reduction in net absorption of sodium chloride and water evoked by vasoactive intestinal peptide (VIP), but did not affect the VIP-evoked increase in net potassium secretion.These findings suggest that PYY acts as an enhancer of sodium chloride and water absorption and as an antagonist to VIP-induced secretion in the colon.     

Inhibition in the rat of gastric acid secretion and cyclic AMP analogs accumulation in vitro by somatostatin.

Various somatostatin (S) analogs exhibited similar degree and similar, or shorter, duration of inhibition of basal gastric acid secretion as S in the unanesthetized rat and similar, or less, inhibition of the cyclic AMP accumulation induced by prostaglandin E2 in the rat anterior pituitary in vitro. With the analogs examined, the gastrointestinal and pituitary receptors appear to exhibit generally similar recognition specificity with the differences within the gastro-intestinal activities reflecting duration of availability rather than receptor affinity.     

Effect of vinblastine on pancreatic enzymes secretion induced by cyclic nucleotide derivatives

Summary Vinblastine did not affect the basal secretion of enzymes from the rat pancreas, but it potentiates the secretory response to dibutyryl cyclic AMP. This potentiation is confirmed by the observation of numerous pictures of exocytosis at the apical part of the acinar cell. Dibutyryl cyclic GMP by itself, or associated with vinblastine, failed to modify the spontaneous release of enzymes or the secretion induced by dibutyryl cyclic AMP.This work was supported by the Institut National de la Santé et de la Recherche Médicale (France).     

Effect of vinblastine on pancreatic enzymes secretion induced by cyclic nucleotide derivatives.

Vinblastine did not affect the basal secretion of enzymes from the rat pancreas, but it potentiates the secretory response to dibutyryl cyclic AMP. This potentiation is confirmed by the observation of numerous pictures of exocytosis at the apical part of the acinar cell. Dibutyryl cyclic GMP by itself, or associated with vinblastine, failed to modify the spontaneous release of enzymes or the secretion induced by dibutyryl cyclic AMP.     

Inhibition in the rat of gastric acid secretion and cyclic AMP analogs accumulation in vitro by somatostatin

Summary Various somatostatin (S) analogs exhibited similar degree and similar, or shorter, duration of inhibition of basal gastric acid secretion as S in the unanesthetized rat and similar, or less, inhibition of the cyclic AMP accumulation induced by prostaglandin E₂ in the rat anterior pituitary in vitro. With the analogs examined, the gastrointestinal and pituitary receptors appear to exhibit generally similar recognition specificity with the differences within the gastrointestinal activities reflecting duration of availability rather than receptor affinity.The author acknowledges the technical assistance of Mr L. Chamberland, Miss A. Colaviti and Miss C. Pilapil.     

Modification of the action of pentagastrin on acid secretion by botulinum toxin.

I.v botulinum toxin after 60-90 min abolished the dose-response relationship between pentagastrin and gastric acid secretion in anesthetized rats and guinea-pigs. The toxin reduced but did not abolish the acid stimulatory effect of histamine. As expected, the acid response to vagal stimulation was abolished and that to methacholine in rats was unaltered by the toxin.     

Factors influencing the intestinal phase of pancreatic exocrine secretion in the turkey

The present study was done to investigate the factors regulating the intestinal phase of exocrine pancreatic secretion in the turkey. The intestine of turkeys equipped with pancreatic fistulas was perfused with peptone solution, fat emulsion and hydrochloric acid (HCl), and pancreatic flow and protein output were measured. Neither peptone solution nor fat emulsion had any effects on pancreatic secretion. HCl enhanced the flow rate of pancreatic juice but not protein output. To clarify the neural mechanism of this phenomenon, the vagal postganglionic blocker atropine was continuously infused and pancreatic secretion in response to intestinal HCl was measured. Atropine completely suppressed both pancreatic flow and protein output. It is suggested that the avian intestinal phase of pancreatic secretion is mainly controlled by cholinergic action though HCl stimulation.     

Stimulation of pyruvate carboxylation by gastric secretagogues

Pyruvate carboxylation was stimulated by 2 gastric secretagogues, histamine and dibutyryl cyclic AMP, and by butyrate. Thiocyanate, an inhibitor of acid secretion, produced a slight decrease. Avidin significantly reduced acid secretion and this effect was overcome by biotin and oxalacetate. The results suggest that carboxylation of pyruvate is one of the reactions controlling oxidative metabolism and acid secretion in toad gastric mucosa.     

Pancreastatin,a chromogranin A-derived peptide,inhibits leptin and enhances UCP-2 expression in isolated rat adipocytes

Leptin, the ob gene product, is an adipocyte-secreted hormone that centrally regulates weight by decreasing caloric intake and increasing energy expenditure. Expression of leptin is regulated by dietary status, insulin, glucocorticoids and catecholamines. Pancreastatin (PST), a chromogranin A-derived peptide, correlates with catecholamine levels, and may play a role in the physiology of stress, modulating endocrine secretion and metabolism. Thus, PST has been found to exert a lipolytic and anti-insulin effect in white adipocytes. The aim of the present work was to investigate a possible role of PST modulating the expression of key genes involved in lipid storage and metabolism: leptin, PPAR-2, UCP-1 and UCP-2. We incubated isolated rat epididymal adipocytes with 100 nM PST for 16 and 24 h. Leptin, UCP-2 and UCP-1 mRNA levels were assessed by RT-PCR, followed by Southern blot. Leptin secretion was also measured by ELISA. PST inhibited leptin expression and secretion at 16-h incubation, but this effect was no longer observed after 24 h. On the other hand, PST stimulated the expression of UCP-2 after 16 h. However, the effect was still significant after 24 h. The inhibitory effect of PST on leptin expression and secretion and the stimulation of UCP-2 expression were prevented by blocking PKC. UCP-1 and PPR-2 expression did not change after PST stimulation. Leptin differentially regulates the expression of key genes in the rat adipocyte, upregulating the expression of UCP-2 and inhibiting the expression and secretion of leptin by a mechanism that involves PKC activity. These effects may contribute to the metabolic action of catecholamines in physiological and pathophysiological conditions with increased sympathetic activity.Received 5 September 2003; received after revision 6 October 2003; accepted 14 October 2003     

Pepsinogens, progastricsins, and prochymosins: structure, function, evolution, and development

Five types of zymogens of pepsins, gastric digestive proteinases, are known: pepsinogens A, B, and F, progastricsin, and prochymosin. The amino acid and/or nucleotide sequences of more than 50 pepsinogens other than pepsinogen B have been determined to date. Phylogenetic analyses based on these sequences indicate that progastricsin diverged first followed by prochymosin, and that pepsinogens A and F are most closely related. Tertiary structures, clarified by X-ray crystallography, are commonly bilobal with a large active-site cleft between the lobes. Two aspartates in the center of the cleft, Asp32 and Asp215, function as catalytic residues, and thus pepsinogens are classified as aspartic proteinases. Conversion of pepsinogens to pepsins proceeds autocatalytically at acidic pH by two different pathways, a one-step pathway to release the intact activation segment directly, and a stepwise pathway through a pseudopepsin(s). The active-site cleft is large enough to accommodate at least seven residues of a substrate, thus forming S₄ through S₃′ subsites. Hydrophobic and aromatic amino acids are preferred at the P₁ and P₁′ positions. Interactions at additional subsites are important in some cases, for example with cleavage of κ-casein by chymosin. Two potent naturally occurring inhibitors are known: pepstatin, a pentapeptide from Streptomyces, and a unique proteinous inhibitor from Ascaris. Pepsinogen genes comprise nine exons and may be multiple, especially for pepsinogen A. The latter and progastricsin predominate in adult animals, while pepsinogen F and prochymosin are the main forms in the fetus/infant. The switching of gene expression from fetal/infant to adult-type pepsinogens during postnatal development is noteworthy, being regulated by several factors, including steroid hormones. Received 25 May 2001; received after revision 27 August 2001; accepted 30 August 2001     

Stimulation of pyruvate carboxylation by gastric secretagogues

Summary Pyruvate carboxylation was stimulated by 2 gastric secretagogues, histamine and dibutyryl cyclic AMP, and by butyrate. Thiocyanate, an inhibitor of acid secretion, produced a slight decrease. Avidin significantly reduced acid secretion and this effect was overcome by biotin and oxalacetate. The results suggest that carboxylation of pyruvate is one of the reactions controlling oxidative metabolism and acid secretion in toad gastric mucosa.This investigation was supported by Consejo de Desarrollo Científico y Humanístico de la Universidad del Zulia, and by CONICIT Grant S1-0455.     

Pancreastatin (33–49) enhances the priming effect of glucose in the rat pancreas

Short-term exposure to glusoe increases insulin secretion during subsequent stimulation. We investigated the effect of the new regulatory peptide pancreastatin on this priming effect of glucose in the perfused rat pancreas. Pancreastatin (33–49) at a concentration of 10^–8 M inhibited insulin release when stimulated by glucose at a concentration of 16.7 mM. However, after a second pulse of 16.7 mM glucose, pancreastatin potentiated the priming effect of glucose on insulin secretion. The modulation of insulin secretion by pancreastatin results in a potentiation of the priming effect of glucose in the rat pancreas, suggesting a role for pancreastatin in the adaptation of the B cell to glucose-stimulated insulin secretion.     

Corticotropin releasing factor increases the adrenocortical responsiveness to adrenocorticotropin

Summary In the course of studying the plasma adrenocorticotropic hormone (ACTH) and corticosterone responses to synthetic corticotropin releasing factor (CRF), we noted some disparity in the responses. A higher dose (20 g compared with 5 g per rat i.a.) produced an equal plasma ACTH but greater plasma corticosterone response in adult male rats. Thus, we examined the possibility that CRF increases adrenocortical responsiveness to ACTH. CRF significantly (p<0.0005) increased the plasma corticosterone response to ACTH in rats pretreated with dexamethasone. Thus, synthetic CRF increases corticosterone secretion in rats not only by stimulating ACTH secretion, but also by increasing the adrenocortical responsiveness to ACTH.Acknowledgments. This research was supported by grant MT-5183 from the Medical Research Council of Canada and by the Department of Medicine, University of Kentucky.     

Neuropeptide Y inhibits corticosterone secretion by isolated rat adrenocortical cells

Summary Studies with isolated rat adrenocortical cells have shown that neuropeptide Y (NPY) inhibits both basal and ACTH-stimulated corticosterone secretion. These results suggest the regulatory role of NPY in corticosterone secretion from the adrenal gland, especially during stress.Supported in part by a grant CPBP 06.03.3.16.     

Effect of monensin and diabetes on asialoglycoprotein degradation in rat hepatocytes.

We have studied the effects of two modulations--streptozotocin-induced diabetes in vivo, and the presence of the carboxylic proton ionophore monensin in vitro--on the degradation of 3H-asialoorosomucoid ligand in isolated rat hepatocytes. The ligand was internalized by means of a synchronous wave procedure. Diabetes was associated with a marked decrease in the amount of total degraded radioactive ligand compared to that in normal cells (3.6% and 37.3% of internalized ligand respectively, at 60 min), together with increased secretion of degradation products into the incubation medium (87% and 46.3% of the total degraded ligand was secreted by diabetic and normal cells, respectively). Monensin induced similar effects in normal cells, but had no apparent effect in diabetic cells.