Isovaleric Acid (IVA) is a 5-carbon branched chain fatty acid present in fermented foods and produced by the fermentation of leucine by colonic bacteria. IVA activates G-protein coupled receptors such as FFAR2, FFAR3, and OR51E1 known to be expressed on enteric neurons and enteroendocrine cells. We previously reported that the shorter, straight chain fatty acids acetate, propionate and butyrate, differentially affect colonic propulsion; however, the effect of branched chain fatty acids on gastrointestinal motility is unknown. We hypothesize that IVA relaxes smooth muscle in a cAMP/PKA dependent manner by direct action on smooth muscle cells. IVA will also decrease peristalsis and encourage retention of luminal contents. This thesis investigates the effect of IVA on smooth muscle tension and peristaltic activity in isolated colon and individual smooth muscle cells. Colon segments from C57BL/6J mice were placed in a longitudinal orientation in organ baths in Krebs buffer and fastened to force transducers. Segments were contracted with 10 μM acetylcholine (ACh) and the effects of IVA at several concentrations were measured in the absence and presence of Nitric Oxide Synthase inhibitor L-N-nitroarginine (L-NNA), neuronal action potential inhibitor tetrodotoxin (TTX), and adenylate cyclase inhibitor SQ22536. To study individual live cells, mouse smooth muscle was isolated from colon, suspended in smooth muscle buffer, and after contraction with ACh were relaxed with micromolar concentrations of IVA. For peristalsis studies, whole colonic segments isolated from C57BL/6J were catheterized and placed horizontally in organ baths with circulating Krebs buffer. The colon was clamped on the anal end, and a solution (5 μL per mm of colon length) of either Krebs buffer or 50 mM IVA was delivered from the oral end to the lumen. Video of the peristalsis was then analyzed for diameter, changes in diameter, velocity of diameter changes along the length of the colon, normalized to the anatomical changes in the proximal region. IVA in concentrations of 10 mM to 50 mM relaxed the ACh-induced contraction in a sigmoidal fashion. In separate studies, L-NNA nor TTX affected the ability of IVA to inhibit relaxation. SQ22536 inhibited IVA induced relaxation in longitudinal colon compared to vehicle control. In isolated cells, SQ22536 and PKA inhibitor H-89 inhibited IVA-induced relaxation. In peristalsis studies, 50 mM IVA in Krebs buffer changed the character of the peristaltic action by increasing proximal diameter, inhibiting contractions in the proximal end of the colon, and decreasing overall velocity of peristaltic contractions in the proximal region. The data indicate that the branched chain fatty acid IVA causes a concentration-dependent relaxation of colonic smooth muscle that is direct to the smooth muscle and independent of neuronal activity. This relaxation is cAMP/PKA dependent. In addition to the direct relaxation of smooth muscle, intraluminal IVA decreased overall colonic propulsive activity and encouraged retention of the luminal contents. We conclude that the ingestion and production of branched chain fatty acids could affect overall GI motility and is an area for study in dietary and therapeutic control of bowel activity.

Les tumeurs endocrines digestives sont des tumeurs hypervasculaires, ce qui suggère l'existence d'un processus d'angiogenèse tumorale actif. Les mécanismes de l'angiogenèse tumorale associée aux tumeurs endocrines digestives sont complexes. Deux processus semblent coexister : les tumeurs les mieux différenciées sont capables de récapituler les propriétés pro-angiogéniques des cellules endocrines normales alors que les tumeurs moins différenciées et plus agressives sont associées à un processus d angiogenèse non spécifique, développé en réponse à l'hypoxie. Dans ces deux processus, le VEGF joue vraisemblablement un rôle important, dans la mesure où il fait partie intégrante du programme de différenciation endocrine. L'objectif de notre travail a été de mieux comprendre les mécanismes de sa régulation dans les cellules endocrines digestives tumorales et d'analyser son rôle dans la croissance tumorale, à travers une double approche expérimentale, in vitro et in vivo ; Nos résultats nous ont permis de : (a) montrer la complexité de la régulation de la synthèse et de la sécrétion du VEGF par les cellules endocrines néoplasiques, qui implique plusieurs voies de signalisation (PI3K/Akt/mTOR et p38/MAPK), dont les rôles respectifs varient selon le type de cellule étudiée ; (b) confirmer expérimentalement la dissociation entre expression du VEGF et capacités angiogéniques d'une part, propriétés invasives et métastatiques d'autre part ; (c) montrer expérimentalement que l'inhibition de l'angiogenèse peut contribuer à l'effet antitumoral de substances d'intérêt thérapeutique dans les tumeurs endocrines digestives / Digestive endocrine tumors are hypervascular tumors, likely to be associated with an active angiogenic process. The mechanisms of tumor angiogenesis in digestive endocrine tumors are complex. Two processes seem to coexist: well differentiated tumors are able to recapitulate the pro-angiogenic capacities of normal endocrine cells whereas less differentiated and more aggressive tumors are associated with a non specific angiogenic process, in response to hypoxia. In both processes, VEGF is likely to play an important role, since it is constitutively expressed by normal peptide-secreting endocrine cells, as part of their specific differentiation program. Our aim was to evaluate the mechanisms of regulation of VEGF synthesis and secretion by neoplastic digestive endocrine tumors and to analyze its role in tumor progression, through an in vitro and in vivo experimental approach. We were able to demonstrate that: (a) the regulation of VEGF synthesis and secretion is complex and involves several pathways (PI3K/Akt/mTOR and p38/MAPK), with different roles according to the cell studied; (b) there is a dissociation between VEGF expression and angiogenic capacities, on one hand, and invasive and metastatic properties, on the other hand; (c) the inhibition of angiogenesis may contribute to the anti-tumoral effect of several drugs of therapeutic interest in digestive endocrine tumors

Includes bibliographical references (leaves 159-213) Shows that IGF-I peptides are effective in diminishing post-surgical catabolism and enhancing adaptive gut hyperplasia in rats recovering from massive small bowel resection.

This thesis presents studies relating to the role of the gastrointestinal tract in postprandial blood pressure regulation. The areas that have been addressed include : ( i ) the methodological approaches to the evaluation of gastric emptying, blood pressure, splanchnic blood flow, intraluminal manometry and gut hormones and ( ii ) the pathophysiological mechanisms underlying postprandial hypotension, with a particular focus on ' gastric ' and ' small intestinal ' mechanisms and their potential therapeutic relevance. All of the studies have been either published or manuscripts have been prepared for publication. While scintigraphy represents the ' gold standard ' for the measurement of gastric emptying, recent studies suggest that three - dimensional ( 3D ) ultrasonography may also allow a precise measure of gastric emptying. Concurrent scintigraphic and ultrasonographic measurements of gastric emptying of liquids were performed in healthy young volunteers. There was a good correlation and agreement between scintigraphic measurements of gastric emptying and 3D ultrasonography after ingestion of both low - and high - nutrient drinks, indicating that 3D ultrasonography, provides a valid measure of gastric emptying of liquid meals in normal subjects. Postprandial hypotension, defined as a fall in systolic blood pressure of ≥ 20mmHg,occurring within two hours of a meal is now recognised as an important clinical problem, particularly in the elderly and in patients with type 2 diabetes. The mechanisms mediating postprandial hypotension are poorly understood. The effects of variations in concentration of intraduodenal glucose on the magnitude of the fall in blood pressure were evaluated in healthy elderly subjects. Blood pressure fell, and heart rate and blood glucose increased over time during infusions, however, there was no difference in blood pressure, heart rate or blood glucose concentrations between the study days. These observations suggest that glucose induced postprandial hypotension is a load rather, than concentration, dependent phenomenon. The effect of meal composition has been reported to influence the hypotensive response to a meal and information relating to the effects of triglyceride and protein on blood pressure is inconsistent. The comparative effects of isocaloric and isovolaemic intraduodenal infusions of glucose, triglyceride and protein on the magnitude of the postprandial fall in blood pressure and rise in heart rate and superior mesenteric artery blood flow were evaluated in healthy elderly subjects. There were comparable falls in systolic blood pressure and rises in heart rate, however, the maximum fall in systolic blood pressure occurred later after triglyceride and protein and the stimulation of superior mesenteric artery blood flow was less after protein. These observations suggest that the relatively slower systolic blood pressure response after triglyceride and protein may potentially reflect the time taken for digestion of triglyceride to free fatty acids and protein to amino acids. Acarbose is an antidiabetic drug that slows both gastric emptying and small intestinal glucose absorption. The effects of acarbose, on blood pressure, heart rate, gastric emptying of, and the glycaemic, insulin, glucagon - like peptide - 1 ( GLP - 1 ) and glucosedependent insulinotropic - polypeptide ( GIP ) responses to, an oral sucrose load were evaluated in healthy elderly subjects. Acarbose attenuated the fall in blood pressure and increase in heart rate induced by oral sucrose. Acarbose slowed gastric emptying and was associated with increased retention in the distal stomach. Stimulation of GLP - 1 may contribute to the slowing of gastric emptying and suppression of postprandial glycaemia by acarbose. These findings suggest that acarbose may represent a therapeutic option for the treatment of patients with postprandial hypotension. Recent studies indicate that gastric distension attenuates the postprandial fall in blood pressure. The effects of gastric distension on blood pressure and heart rate during intraduodenal infusion of glucose at a constant load and concentration were evaluated in healthy elderly subjects. Intragastric administration of water markedly attenuated the falls in systolic and diastolic blood pressure induced by intraduodenal glucose. Heart rate increased, with and without gastric distension, in response to intraduodenal glucose infusion but not after intraduodenal saline infusion. This study suggests that gastric distension may potentially be used as a simple adjunctive treatment in the management of postprandial hypotension. Studies employing nitric oxide synthase blockers have established, in animals, that nitric oxide mechanisms are important in the regulation of splanchnic blood flow and, hence, may effect postprandial blood pressure. The role of the nitric oxide synthase inhibitor, NG - nitro - L - arginine - methyl - ester ( L - NAME ), on gastric emptying, postprandial blood pressure, plasma insulin concentration and incretin hormone ( ie GIP and GLP - 1 ) release, following an oral glucose load, were evaluated in healthy elderly subjects. L - NAME attenuated the postprandial fall in blood pressure and increase in heart rate but had no effect on gastric emptying of glucose. L - NAME attenuated the glucose - induced rise in plasma insulin but had no effect on the incretin ( GIP and GLP - 1 ) hormone response to oral glucose. The study indicates that the magnitude of the fall in blood pressure and increase in heart rate and stimulation of insulin secretion induced by oral glucose in healthy elderly subjects are mediated by nitric oxide mechanisms by an effect unrelated to changes in gastric emptying, or the secretion of GIP and GLP - 1. Studies utilising 5 - hydroxytryptamine ( 5 - HT ) infusions in animals have demonstrated regional variations in intestinal blood flow suggesting a role for 5 - HT in postprandial haemodynamic responses. The effects of the 5 - hydroxytryptamine 3 ( 5 - HT3 ) antagonist, granisetron, on the blood pressure, heart rate, antropyloroduodenal motility and glycaemic responses to intraduodenal glucose infusion were assessed in healthy elderly subjects. Granisetron had no effect on blood pressure, heart rate or antral and pyloric motor responses but modulated the duodenal motor response, to intraduodenal glucose. This study indicates that while the cardiovascular response to intraduodenal glucose does not appear to be influenced by the stimulation of 5 - HT3 receptors, this receptor may be involved in the modulation of the duodenal motor activity. / Thesis (Ph.D.)--School of Medicine, 2006.

xxiii, 222 leaves : ill., plates ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Shows that IGF-I peptides are effective in diminishing post-surgical catabolism and enhancing adaptive gut hyperplasia in rats recovering from massive small bowel resection. / Thesis (Ph.D.)--University of Adelaide, Dept. of Animal Science, 1992

published_or_final_version / abstract / toc / Medicine / Master / Master of Philosophy

This thesis presents studies relating to the role of the gastrointestinal tract in postprandial blood pressure regulation. The areas that have been addressed include : ( i ) the methodological approaches to the evaluation of gastric emptying, blood pressure, splanchnic blood flow, intraluminal manometry and gut hormones and ( ii ) the pathophysiological mechanisms underlying postprandial hypotension, with a particular focus on ' gastric ' and ' small intestinal ' mechanisms and their potential therapeutic relevance. All of the studies have been either published or manuscripts have been prepared for publication. While scintigraphy represents the ' gold standard ' for the measurement of gastric emptying, recent studies suggest that three - dimensional ( 3D ) ultrasonography may also allow a precise measure of gastric emptying. Concurrent scintigraphic and ultrasonographic measurements of gastric emptying of liquids were performed in healthy young volunteers. There was a good correlation and agreement between scintigraphic measurements of gastric emptying and 3D ultrasonography after ingestion of both low - and high - nutrient drinks, indicating that 3D ultrasonography, provides a valid measure of gastric emptying of liquid meals in normal subjects. Postprandial hypotension, defined as a fall in systolic blood pressure of ≥ 20mmHg,occurring within two hours of a meal is now recognised as an important clinical problem, particularly in the elderly and in patients with type 2 diabetes. The mechanisms mediating postprandial hypotension are poorly understood. The effects of variations in concentration of intraduodenal glucose on the magnitude of the fall in blood pressure were evaluated in healthy elderly subjects. Blood pressure fell, and heart rate and blood glucose increased over time during infusions, however, there was no difference in blood pressure, heart rate or blood glucose concentrations between the study days. These observations suggest that glucose induced postprandial hypotension is a load rather, than concentration, dependent phenomenon. The effect of meal composition has been reported to influence the hypotensive response to a meal and information relating to the effects of triglyceride and protein on blood pressure is inconsistent. The comparative effects of isocaloric and isovolaemic intraduodenal infusions of glucose, triglyceride and protein on the magnitude of the postprandial fall in blood pressure and rise in heart rate and superior mesenteric artery blood flow were evaluated in healthy elderly subjects. There were comparable falls in systolic blood pressure and rises in heart rate, however, the maximum fall in systolic blood pressure occurred later after triglyceride and protein and the stimulation of superior mesenteric artery blood flow was less after protein. These observations suggest that the relatively slower systolic blood pressure response after triglyceride and protein may potentially reflect the time taken for digestion of triglyceride to free fatty acids and protein to amino acids. Acarbose is an antidiabetic drug that slows both gastric emptying and small intestinal glucose absorption. The effects of acarbose, on blood pressure, heart rate, gastric emptying of, and the glycaemic, insulin, glucagon - like peptide - 1 ( GLP - 1 ) and glucosedependent insulinotropic - polypeptide ( GIP ) responses to, an oral sucrose load were evaluated in healthy elderly subjects. Acarbose attenuated the fall in blood pressure and increase in heart rate induced by oral sucrose. Acarbose slowed gastric emptying and was associated with increased retention in the distal stomach. Stimulation of GLP - 1 may contribute to the slowing of gastric emptying and suppression of postprandial glycaemia by acarbose. These findings suggest that acarbose may represent a therapeutic option for the treatment of patients with postprandial hypotension. Recent studies indicate that gastric distension attenuates the postprandial fall in blood pressure. The effects of gastric distension on blood pressure and heart rate during intraduodenal infusion of glucose at a constant load and concentration were evaluated in healthy elderly subjects. Intragastric administration of water markedly attenuated the falls in systolic and diastolic blood pressure induced by intraduodenal glucose. Heart rate increased, with and without gastric distension, in response to intraduodenal glucose infusion but not after intraduodenal saline infusion. This study suggests that gastric distension may potentially be used as a simple adjunctive treatment in the management of postprandial hypotension. Studies employing nitric oxide synthase blockers have established, in animals, that nitric oxide mechanisms are important in the regulation of splanchnic blood flow and, hence, may effect postprandial blood pressure. The role of the nitric oxide synthase inhibitor, NG - nitro - L - arginine - methyl - ester ( L - NAME ), on gastric emptying, postprandial blood pressure, plasma insulin concentration and incretin hormone ( ie GIP and GLP - 1 ) release, following an oral glucose load, were evaluated in healthy elderly subjects. L - NAME attenuated the postprandial fall in blood pressure and increase in heart rate but had no effect on gastric emptying of glucose. L - NAME attenuated the glucose - induced rise in plasma insulin but had no effect on the incretin ( GIP and GLP - 1 ) hormone response to oral glucose. The study indicates that the magnitude of the fall in blood pressure and increase in heart rate and stimulation of insulin secretion induced by oral glucose in healthy elderly subjects are mediated by nitric oxide mechanisms by an effect unrelated to changes in gastric emptying, or the secretion of GIP and GLP - 1. Studies utilising 5 - hydroxytryptamine ( 5 - HT ) infusions in animals have demonstrated regional variations in intestinal blood flow suggesting a role for 5 - HT in postprandial haemodynamic responses. The effects of the 5 - hydroxytryptamine 3 ( 5 - HT3 ) antagonist, granisetron, on the blood pressure, heart rate, antropyloroduodenal motility and glycaemic responses to intraduodenal glucose infusion were assessed in healthy elderly subjects. Granisetron had no effect on blood pressure, heart rate or antral and pyloric motor responses but modulated the duodenal motor response, to intraduodenal glucose. This study indicates that while the cardiovascular response to intraduodenal glucose does not appear to be influenced by the stimulation of 5 - HT3 receptors, this receptor may be involved in the modulation of the duodenal motor activity. / Thesis (Ph.D.)--School of Medicine, 2006.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2006. / Härtill 4 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2004. / Härtill 6 uppsatser.

Diss. (sammanfattning) Uppsala : Sveriges lantbruksuniv. / Härtill 4 uppsatser.