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Panganiban RAM, Yang Z, Sun M, Park CY, Kasahara DI, Schaible N, Krishnan R, Kho AT, Israel E, Hershenson MB, Weiss ST, Himes BE, Fredberg JJ, Tantisira KG, Shore SA, Lu Q. Antagonizing cholecystokinin A receptor in the lung attenuates obesity-induced airway hyperresponsiveness. Nat Commun 2023; 14:47. [PMID: 36599824 PMCID: PMC9813361 DOI: 10.1038/s41467-022-35739-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Accepted: 12/21/2022] [Indexed: 01/06/2023] Open
Abstract
Obesity increases asthma prevalence and severity. However, the underlying mechanisms are poorly understood, and consequently, therapeutic options for asthma patients with obesity remain limited. Here we report that cholecystokinin-a metabolic hormone best known for its role in signaling satiation and fat metabolism-is increased in the lungs of obese mice and that pharmacological blockade of cholecystokinin A receptor signaling reduces obesity-associated airway hyperresponsiveness. Activation of cholecystokinin A receptor by the hormone induces contraction of airway smooth muscle cells. In vivo, cholecystokinin level is elevated in the lungs of both genetically and diet-induced obese mice. Importantly, intranasal administration of cholecystokinin A receptor antagonists (proglumide and devazepide) suppresses the airway hyperresponsiveness in the obese mice. Together, our results reveal an unexpected role for cholecystokinin in the lung and support the repurposing of cholecystokinin A receptor antagonists as a potential therapy for asthma patients with obesity.
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Affiliation(s)
- Ronald Allan M Panganiban
- Program in Molecular and Integrative Physiological Sciences, Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, 02115, USA
| | - Zhiping Yang
- Program in Molecular and Integrative Physiological Sciences, Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, 02115, USA
| | - Maoyun Sun
- Program in Molecular and Integrative Physiological Sciences, Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, 02115, USA
| | - Chan Young Park
- Program in Molecular and Integrative Physiological Sciences, Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, 02115, USA
| | - David I Kasahara
- Program in Molecular and Integrative Physiological Sciences, Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, 02115, USA
| | - Niccole Schaible
- Emergency Medicine, Beth Israel Deaconess Medical Center, Boston, MA, 02115, USA
| | - Ramaswamy Krishnan
- Emergency Medicine, Beth Israel Deaconess Medical Center, Boston, MA, 02115, USA
| | - Alvin T Kho
- Computational Health informatics Program, Boston Children's Hospital, Boston, MA, 02115, USA
| | - Elliot Israel
- Asthma Research Center, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA
| | - Marc B Hershenson
- Department of Pediatrics and Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, 48109, USA
| | - Scott T Weiss
- Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA
| | - Blanca E Himes
- Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Jeffrey J Fredberg
- Program in Molecular and Integrative Physiological Sciences, Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, 02115, USA
| | - Kelan G Tantisira
- Division of Pediatric Respiratory Medicine, University of California San Diego and Rady Children's Hospital, San Diego, CA, 92123, USA
| | - Stephanie A Shore
- Program in Molecular and Integrative Physiological Sciences, Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, 02115, USA
| | - Quan Lu
- Program in Molecular and Integrative Physiological Sciences, Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, 02115, USA.
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Jaffey JA. Feline cholangitis/cholangiohepatitis complex - what have we learned? J Small Anim Pract 2022; 63:573-589. [PMID: 35522164 DOI: 10.1111/jsap.13508] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Revised: 02/19/2022] [Accepted: 04/11/2022] [Indexed: 12/07/2022]
Abstract
Cholangitis/cholangiohepatitis complex in cats is commonly encountered in clinical practice worldwide. Diagnosis and management of cats with this complex is difficult because of the ambiguity of clinical signs, diagnostic test results and commonality of comorbid disorders. These impediments can delay disease identification and treatment, which can increase morbidity and mortality. In this narrative review, we aimed to provide a thorough review of the unique physioanatomic features of the biliary system as well as clinically relevant updates on cholangitis/cholangiohepatitis complex in cats.
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Affiliation(s)
- J A Jaffey
- Department of Specialty Medicine, College of Veterinary Medicine, Midwestern University, Glendale, Arizona, 85308, USA
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Ren LK, Cai ZY, Ran X, Yang NH, Li XZ, Liu H, Wu CW, Zeng WY, Han M. Evaluating the efficacy of endoscopic sphincterotomy on biliary-type sphincter of Oddi dysfunction: A retrospective clinical trial. World J Clin Cases 2021; 9:9835-9846. [PMID: 34877322 PMCID: PMC8610902 DOI: 10.12998/wjcc.v9.i32.9835] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Revised: 07/18/2021] [Accepted: 09/01/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Although endoscopic sphincterotomy (EST) has a positive therapeutic effect on biliary-type sphincter of Oddi dysfunction (SOD), some patients still have little relief after EST, which implies that other functional abdominal pain may also be present with biliary-type SOD and interfere with the diagnosis and treatment of it.
AIM To retrospectively assess EST as a treatment for biliary-type SOD and analyze the importance of functional gastrointestinal disorder (FGID) in guiding endoscopic treatment of SOD.
METHODS Clinical data of 79 patients with biliary-type SOD (type I and type II) treated with EST at Affiliated Hospital of Guizhou Medical University from January 2014 to January 2019 were retrospectively collected to evaluate the clinical therapeutic effect of EST. The significance of relationship between FGID and biliary-type SOD was analyzed.
RESULTS Seventy-nine patients with biliary-type SOD received EST, including 29 type 1 patients and 50 type 2 patients. The verbal rating scale-5 (VRS-5) scores before EST were all 3 or 4 points, and the scores decreased after EST; the difference was statistically significant (P < 0.05). After EST, the serum indexes of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase and total bilirubin in biliary-type SOD were significantly lower than before (P < 0.05). After EST, 67 (84.8%) and 8 (10.1%) of the 79 patients with biliary-type SOD had obviously effective (VRS-5 = 0 points) and effective treatment (VRS-5 = 1-2 points), with an overall effectiveness rate of 94.9% (75/79). There was no difference in VRS-5 scores between biliary-type SOD patients with or without FGID before EST (P > 0.05). Of 12 biliary-type SOD (with FGID) patients, 11 had abdominal pain after EST; of 67 biliary-type SOD (without FGID) patients, 0 had abdominal pain after EST. The difference was statistically significant (P <0.05). The 11 biliary-type SOD (with FGID) patients with recurrence of symptoms, the recurrence time was about half a year after the EST, and the symptoms were significantly relieved after regular medical treatment. There were 4 cases of post-endoscopic retrograde cholangiopancreatography pancreatitis (5.1%), and no cholangitis, bleeding or perforation occurred. Patients were followed up for 1 year to 5 years after EST, with an average follow-up time of 2.34 years, and there were no long-term adverse events such as sphincter of Oddi restenosis or cholangitis caused by intestinal bile reflux during the follow-up.
CONCLUSION EST is a safe and effective treatment for SOD. For patients with type I and II SOD combined with FGID, single EST or medical treatment has limited efficacy. It is recommended that EST and medicine be combined to improve the cure rate of such patients.
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Affiliation(s)
- Li-Kun Ren
- Department of General Surgery, The Second Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang 550025, Guizhou Province, China
| | - Zhi-Yuan Cai
- Department of General Surgery, The Second Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang 550025, Guizhou Province, China
| | - Xun Ran
- Department of Hepatobiliary Surgery, Affiliated Hospital of Guizhou Medical University, Guiyang 550000, Guizhou Province, China
| | - Neng-Hong Yang
- Department of Hepatobiliary Surgery, Affiliated Hospital of Guizhou Medical University, Guiyang 550000, Guizhou Province, China
| | - Xing-Zhi Li
- Department of Hepatobiliary Surgery, Affiliated Hospital of Guizhou Medical University, Guiyang 550000, Guizhou Province, China
| | - Hao Liu
- Department of Hepatobiliary Surgery, Affiliated Hospital of Guizhou Medical University, Guiyang 550000, Guizhou Province, China
| | - Chang-Wei Wu
- Department of General Surgery, The First People’s Hospital of Bijie City, Bijie 551700, Guizhou Province, China
| | - Wen-Ying Zeng
- Department of Hepatobiliary Surgery, Affiliated Hospital of Guizhou Medical University, Guiyang 550000, Guizhou Province, China
| | - Min Han
- Department of Hepatobiliary Surgery, Affiliated Hospital of Guizhou Medical University, Guiyang 550000, Guizhou Province, China
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Yang Y, Wang K, Wang CM. Current situation and problems in diagnosis and treatment of sphincter of Oddi dysfunction. Shijie Huaren Xiaohua Zazhi 2018; 26:1735-1741. [DOI: 10.11569/wcjd.v26.i30.1735] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Sphincter of Oddi dysfunction (SOD) is a clinical syndrome referring to the loss of normal physiological function of the sphincter of Oddi with upper abdominal pain from the gallbladder and pancreas, postprandial abdominal bloating, elevation of liver or pancreatic enzymes, common bile duct dilation, pancreatitis and so on. SOD is more common in patients after cholecystectomy. Although the established criteria for diagnosing and treating SOD have been applied in clinical practice, its diagnosis and treatment have long been a controversial topic since the best diagnostic and treatment methods are still unconfirmed, partly because of its natural course, disease treatment process, and long-term follow-up outcomes that have not been determined in large controlled studies. This article briefly reviews the latest research of SOD and comprehensively analyzes the current status and existing problems in the diagnosis and treatment of SOD, with an aim to provide appropriate advice for clinicians to diagnose and treat this disease.
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Affiliation(s)
- Ying Yang
- Department of General Surgery, the First Affiliated Hospital of Dalian Medical University, Dalian 116011, Liaoning Province, China
| | - Kai Wang
- Department of General Surgery, the First Affiliated Hospital of Dalian Medical University, Dalian 116011, Liaoning Province, China
| | - Chang-Miao Wang
- Department of General Surgery, the First Affiliated Hospital of Dalian Medical University, Dalian 116011, Liaoning Province, China
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Afghani E, Lo SK, Covington PS, Cash BD, Pandol SJ. Sphincter of Oddi Function and Risk Factors for Dysfunction. Front Nutr 2017; 4:1. [PMID: 28194398 PMCID: PMC5276812 DOI: 10.3389/fnut.2017.00001] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2016] [Accepted: 01/10/2017] [Indexed: 12/14/2022] Open
Abstract
The sphincter of Oddi (SO) is a smooth muscle valve regulating the flow of biliary and pancreatic secretions into the duodenum, initially described in 1887 by the Italian anatomist, Ruggero Oddi. SO dysfunction (SOD) is a broad term referring to numerous biliary, pancreatic, and hepatic disorders resulting from spasms, strictures, and relaxation of this valve at inappropriate times. This review brings attention to various factors that may increase the risk of SOD, including but not limited to: cholecystectomy, opiates, and alcohol. Lack of proper recognition and treatment of SOD may be associated with clinical events, including pancreatitis and biliary symptoms with hepatic enzyme elevation. Pharmacologic and non-pharmacologic approaches are discussed to help recognize, prevent, and treat SOD. Future studies are needed to assess the treatment benefit of agents such as calcium-channel blockers, glyceryl trinitrate, or tricyclic antidepressants in patients with SOD.
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Affiliation(s)
| | - Simon K. Lo
- Cedars-Sinai Medical Center, Los Angeles, CA, USA
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Kyanam Kabir Baig KR, Wilcox CM. Translational and clinical perspectives on sphincter of Oddi dysfunction. Clin Exp Gastroenterol 2016; 9:191-5. [PMID: 27555792 PMCID: PMC4968664 DOI: 10.2147/ceg.s84018] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Sphincter of Oddi dysfunction is a complex pathophysiologic entity that is associated with significant morbidity causing abdominal pain, nausea, and vomiting. The purpose of this review is to describe the anatomy and physiology of the sphincter of Oddi, to understand the pathologic mechanisms thought to be responsible for symptomatology, review recent major studies, explore endoscopic and pharmacologic therapies and their efficacy, and to explore future research avenues.
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Affiliation(s)
- Kondal Rao Kyanam Kabir Baig
- Division of Gastroenterology and Hepatology, University of Alabama
- Birmingham VA Medical Center, Birmingham, AL, USA
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Rong ZH, Chen HY, Wang XX, Wang ZY, Xian GZ, Ma BZ, Qin CK, Zhang ZH. Effects of sphincter of Oddi motility on the formation of cholesterol gallstones. World J Gastroenterol 2016; 22:5540-5547. [PMID: 27350732 PMCID: PMC4917614 DOI: 10.3748/wjg.v22.i24.5540] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2016] [Revised: 03/30/2016] [Accepted: 04/20/2016] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the mechanisms and effects of sphincter of Oddi (SO) motility on cholesterol gallbladder stone formation in guinea pigs.
METHODS: Thirty-four adult male Hartley guinea pigs were divided randomly into two groups, the control group (n = 10) and the cholesterol gallstone group (n = 24), which was sequentially divided into four subgroups with six guinea pigs each according to time of sacrifice. The guinea pigs in the cholesterol gallstone group were fed a cholesterol lithogenic diet and sacrificed after 3, 6, 9, and 12 wk. SO manometry and recording of myoelectric activity were obtained by a multifunctional physiograph at each stage. Cholecystokinin-A receptor (CCKAR) expression levels in SO smooth muscle were detected by quantitative real-time PCR (qRT-PCR) and serum vasoactive intestinal peptide (VIP), gastrin, and cholecystokinin octapeptide (CCK-8) were detected by enzyme-linked immunosorbent assay at each stage in the process of cholesterol gallstone formation.
RESULTS: The gallstone formation rate was 0%, 0%, 16.7%, and 83.3% in the 3, 6, 9, and 12 wk groups, respectively. The frequency of myoelectric activity in the 9 wk group, the amplitude of myoelectric activity in the 9 and 12 wk groups, and the amplitude and the frequency of SO in the 9 wk group were all significantly decreased compared to the control group. The SO basal pressure and common bile duct pressure increased markedly in the 12 wk group, and the CCKAR expression levels increased in the 6 and 12 wk groups compared to the control group. Serum VIP was elevated significantly in the 9 and 12 wk groups and gastrin decreased significantly in the 3 and 9 wk groups. There was no difference in serum CCK-8 between the groups.
CONCLUSION: A cholesterol gallstone-causing diet can induce SO dysfunction. The increasing tension of the SO along with its decreasing activity may play an important role in cholesterol gallstone formation. Expression changes of CCKAR in SO smooth muscle and serum VIP and CCK-8 may be important causes of SO dysfunction.
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Li W, Hill N, Ogden R, Smythe A, Majeed A, Bird N, Luo X. Anisotropic behaviour of human gallbladder walls. J Mech Behav Biomed Mater 2013; 20:363-75. [DOI: 10.1016/j.jmbbm.2013.02.015] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2012] [Revised: 02/11/2013] [Accepted: 02/20/2013] [Indexed: 10/27/2022]
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Physiology and Pathophysiology of the Biliary Tract: The Gallbladder and Sphincter of Oddi—A Review. ACTA ACUST UNITED AC 2013. [DOI: 10.1155/2013/837630] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
The biliary tract collects, stores, concentrates, and delivers bile secreted by the liver. Its motility is controlled by neurohormonal mechanisms with the vagus and splanchnic nerves and the hormone cholecystokinin playing key roles. These neurohormonal mechanisms integrate the motility of the gallbladder and sphincter of Oddi (SO) with the gastrointestinal tract in the fasting and digestive phases. During fasting most of the hepatic bile is diverted toward the gallbladder by the resistance of the SO. The gallbladder allows the gradual entry of bile relaxing by passive and active mechanisms. During the digestive phase the gallbladder contracts, and the SO relaxes allowing bile to be released into the duodenum for the digestion and absorption of fats. Pathological processes manifested by recurrent episodes of upper abdominal pain affect both the gallbladder and SO. The gallbladder motility and cytoprotective functions are impaired by lithogenic hepatic bile with excess cholesterol allowing the hydrophobic bile salts to induce chronic cholecystitis. Laparoscopic cholecystectomy is the standard treatment. Three types of SO dyskinesia also cause biliary pain. Their pathophysiology is not completely known. The pain of types I and II usually respond to sphincterotomy, but the pain due to type III usually does not.
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The distribution and chemical coding of neurons supplying the sphincter of Oddi in mammals. Pol J Vet Sci 2013; 16:787-96. [PMID: 24597319 DOI: 10.2478/pjvs-2013-0113] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
The major duodenal papilla (papilla of Vater) is an important structure associated with the biliary tract and, in some species, the pancreas. It usually represents a slight elevation on the intestinal mucosa where the dilated junction (ampulla of Vater) of the commmon bile duct and pancreatic duct enters the duodenum. The ampulla is surrounded by a specifically arranged muscle structure called the sphincter of Oddi (SO) which controls the flow of bile and pancreatic fluid. The function of the sphincter is regulated by a complex system that involves many hormonal and neural factors. The literature in the field contains detailed data on the morphology of the SO in a number of mammalian species. However, the comprehensive information about the anatomy and neurochemistry of the innervation of this structure is very limited. The present review article summarizes the current knowledge on the innervation of the SO in mammals. Special emphasis has been put on the localization and chemical coding of neurons contributing to this nerve supply.
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Abstract
OBJECTIVE To determine the effect of cholecystectomy on the motility of the sphincter of Oddi (SO). METHODS Pressures of common bile duct (CBD), SO motility and its response to bolus injections of cholecystokinin (CCK, 20 ng/kg and 100 ng/kg) were detected respectively by manometry in eight Beagle dogs before and after cholecystectomy. RESULTS After cholecystectomy the CBD pressure increased 2.18 ± 1.86 mmHg, while the cyclical motion pattern of SO still existed but with a shortened cycle duration. The basal pressure (BP), phasic contraction amplitude (PCA), phasic contraction frequency (PCF) and its mode of propagation did not change significantly. Under the stimulation of CCK after cholecystectomy, although the motion patterns of SO were similar to those before cholecystectomy, the greatest inhibitory efficacy of BP and PCA all decreased with the prolonged excitement duration and the increased percentage of retrograde contraction. CONCLUSIONS Shortly after a cholecystectomy in Beagle dogs, the CBD pressure increased, SO motilities did not change significantly during the interdigestive phase except with a shortened cycle duration. Its relaxation responded to CCK was weakened with a confused contraction pattern.
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Affiliation(s)
- Ming Ming Fan
- Department of General Surgery, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
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Furneaux RW. A series of six cases of sphincter of Oddi pathology in the cat (2008-2009). J Feline Med Surg 2010; 12:794-801. [PMID: 20817527 PMCID: PMC11135523 DOI: 10.1016/j.jfms.2010.06.004] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/09/2010] [Indexed: 12/14/2022]
Abstract
The sphincter of Oddi (SO) is located within the wall of the duodenum as the terminal part of the common bile duct. Six cats are reported with obstructive processes within their SO. Three of them may have had some form of sphincter dysfunction associated with the pre-existing complex known as 'inflammatory bowel disease' (IBD), two may have had the equivalent of the infant human condition known as 'bile plug syndrome' and the sixth had sphincter dysfunction associated with a tumour at the confluence of the common and right hepatic duct. In all six cases, the sphincter obstructions were surgically managed. The outcomes for 4/6 were favourable but 1/6 was euthanased intraoperatively, and 1/6 had a metastatic neoplasia and was euthanased 2 months postoperatively.
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Affiliation(s)
- Robert W Furneaux
- School of Veterinary Science, 250 Princes Highway, Werribee, Victoria 3030, Australia.
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Copps J, Murphy RF, Lovas S. The production and role of gastrin-17 and gastrin-17-gly in gastrointestinal cancers. Protein Pept Lett 2010; 16:1504-18. [PMID: 20001914 DOI: 10.2174/092986609789839269] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The gastrointestinal peptide hormone gastrin is responsible for initiating the release of gastric acid in the stomach in response to the presence of food and/or humoral factors such as gastrin releasing peptide. However, it has a role in the growth and maintenance of the gastric epithelium, and has been implicated in the formation and growth of gastric cancers. Hypergastrinemia resulting from atrophic gastritis and pernicious anemia leads to hyperplasia and carcinoid formation in rats, and contributes to tumor formation in humans. Additionally, gastrin has been suspected to play a role in the formation and growth of cancers of the colon, but recent studies have instead implicated gastrin processing intermediates, such as gastrin-17-Gly, acting upon a putative, non-cholecystokinin receptor. This review summarizes the production and chemical structures of gastrin and of the processing intermediate gastrin-17-Gly, as well as their activities in the gastrointestinal tract, particularly the promotion of colon cancers.
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Affiliation(s)
- Jeffrey Copps
- Department of Biomedical Sciences, Creighton University School of Medicine, 2500 California Plaza, Omaha, NE 68178, USA
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Affiliation(s)
- Antonio Bosch
- Division of Digestive Diseases and Nutrition, University of Kentucky Chandler Medical Center, Lexington, KY 40536-0298, USA.
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Kofuji PYM, Murashita K, Hosokawa H, Masumoto T. Effects of exogenous cholecystokinin and gastrin on the secretion of trypsin and chymotrypsin from yellowtail (Seriola quinqueradiata) isolated pyloric caeca. Comp Biochem Physiol A Mol Integr Physiol 2007; 146:124-30. [PMID: 17126578 DOI: 10.1016/j.cbpa.2006.09.017] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2005] [Revised: 09/19/2006] [Accepted: 09/25/2006] [Indexed: 11/28/2022]
Abstract
The humoral control of secretion of the proteolytic enzymes trypsin and chymotrypsin was studied in yellowtail (Seriola quinqueradiata). In vitro trials were performed to investigate the effects of cholecystokinin (CCK) and two commercially available gastrin peptides. Isolated preparations of pyloric caeca/pancreas release trypsin and chymotrypsin when incubated with cholecystokinin (CCK) at 10 microM and gastrin I (G1) at 50 microM after 15 min of incubation. On the other hand, G1 at 10 microM and gastrin-related peptide (G2) did not enhance trypsin and chymotrypsin secretion. The studies concerning the CCK effects at different incubation temperatures have shown that trypsin and chymotrypsin secretion at 25 degrees C was stimulated by CCK after 15 min, while at 10, 15 and 20 degrees C the stimulatory effects of CCK were observed only after 30 min of incubation. The CCK effects were increased at higher incubation temperatures and longer incubation periods.
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Affiliation(s)
- Patricia Y M Kofuji
- Laboratory of Fish Nutrition, Faculty of Agriculture, Kochi University, Monobe 200, Nankoku, Kochi 783-8502, Japan
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Murashita K, Fukada H, Hosokawa H, Masumoto T. Changes in cholecystokinin and peptide Y gene expression with feeding in yellowtail (Seriola quinqueradiata): relation to pancreatic exocrine regulation. Comp Biochem Physiol B Biochem Mol Biol 2006; 146:318-25. [PMID: 17208482 DOI: 10.1016/j.cbpb.2006.11.009] [Citation(s) in RCA: 56] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2006] [Revised: 11/08/2006] [Accepted: 11/12/2006] [Indexed: 11/20/2022]
Abstract
In fish, the regulation of digestive enzyme secretion by hormonal control such as cholecystokinin (CCK) and neuropeptide Y (NPY)-related peptide is not well understood. To investigate the roles of fish CCK and peptide Y (PY) in digestive enzyme secretion, mRNA levels of CCK and PY, pyloric caeca enzyme activities and mRNA levels of pancreatic digestive enzymes (lipase, trypsin and amylase) were measured at pre- and post-prandial stages in yellowtail. Pyloric caeca were sampled at 0, 0.5, 1.5, 3, 6, 12, 24 and 48 h after feeding. The mRNA levels of trypsin and amylase increased after feeding, suggesting that transcription was induced by feed ingestion. Digestive enzyme activities decreased in exocrine pancreas after feeding, suggesting the stored enzyme was secreted from pancreas post-prandially. mRNA levels for CCK displayed a time-dependent increase, peaking between 1.5 and 3 h after-feeding followed by a rapid decrease 3 to 6 h after feeding. The mRNA expression pattern of PY was inverse to the pattern of CCK, decreasing until 1.5 h after feeding and then rising to initial levels by 12 h after feeding. These results suggest that CCK and PY work antagonistically in the exocrine pancreas of yellowtail.
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Affiliation(s)
- Koji Murashita
- Faculty of Agriculture, Kochi University, B200 Monobe, Nankoku, Kochi 783-8502, Japan
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Büyükafşar K, Akça T, Nalan Tiftik R, Sahan-Firat S, Aydin S. Contribution of Rho-kinase in human gallbladder contractions. Eur J Pharmacol 2006; 540:162-7. [PMID: 16730697 DOI: 10.1016/j.ejphar.2006.04.028] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2006] [Revised: 04/11/2006] [Accepted: 04/25/2006] [Indexed: 01/19/2023]
Abstract
Rho/Rho-kinase-mediated pathway has been involved in a variety of physiological processes, including Ca2+ sensitization, which enhances smooth muscle contraction. In this study, first of all we investigated the expression of Rho-kinase (ROCK-2) and then the role of this protein in the control of smooth muscle contraction in the isolated human gallbladder. For this purpose, we examined the effects of a selective Rho-kinase inhibitor, (+)- (R)-trans-4-(1-aminoethyl)-N-(4-pyridyl) cyclohexanecarboxamide dihydrochloride monohydrate (Y-27632, 10(-8)-3x10(-5) M) on carbachol (10(-8)-10(-4) M), cholecystokinin-8 (10(-8) M), endothelin-1 (10(-8) M), histamine (10(-5) M), neurokinin A (10(-7)-10(-6) M), 5-hydroxytryptamine (10(-6)-10(-5) M) and potassium chloride (KCl, 25-50 mM)-induced contractions as well as spontaneous contractile activity. Y-27632 (10(-5) M) significantly reduced 5-hydroxytryptamine, neurokinin A and KCl-induced contractions. Moreover, this Rho-kinase inhibitor (10(-8)-3x10(-5) M, cumulatively) relaxed the contractions produced by cholecystokinin-8, endothelin-1 and histamine in a concentration-dependent manner, being the pEC50 values for Y-27632 5.74+/-0.12, 5.33+/-0.09 and 5.95+/-0.18, respectively. Carbachol (10(-8)-10(-4) M) produced concentration-dependent contractions, which were also inhibited significantly by Y-27632. In addition, the spontaneous contractile activity was suppressed in the presence of Y-27632 (10(-6)-10(-5) M). Moreover, Western blot analysis has revealed that Rho-kinase is expressed in homogenates of the human gallbladder. Taken together, these results show that Rho-kinase is expressed in the human gallbladder, and it has an essential role in agonists and depolarization-induced contractions as well as spontaneous contractile activity.
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Affiliation(s)
- Kansu Büyükafşar
- Department of Pharmacology, Medical Faculty, Mersin University, Campus Yenişehir 33169 Mersin, Turkey.
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Funch-Jensen P, Drewes AM, Madácsy L. Evaluation of the biliary tract in patients with functional biliary symptoms. World J Gastroenterol 2006; 12:2839-45. [PMID: 16718807 PMCID: PMC4087799 DOI: 10.3748/wjg.v12.i18.2839] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The aim of this paper was to describe functional biliary syndromes and methods for evaluation of the biliary tract in these patients. Functional biliary symptoms can be defined as biliary symptoms without demonstrable organic substrate. Two main syndromes exist: Gallbladder dysfunction and sphincter of Oddi dysfunction. The most important investigative tools are cholescintigraphy and endoscopic sphincter of Oddi manometry. In gallbladder dysfunction a scintigraphic gallbladder ejection fraction below 35% can select patients who will benefit from cholecystectomy. Endoscopic sphincter of Oddi manometry is considered the gold standard in sphincter of Oddi dysfunction but recent development in scintigraphic methods is about to change this. Thus, calculation of hilum-to-duodenum transit time and duodenal appearance time on cholescintigraphy have proven useful in these patients. In conclusion, ambient methods can diagnose functional biliary syndromes. However, there are still a number of issues where further knowledge is needed. Probably the next step forward will be in the area of sensory testing and impedance planimetric methods.
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Affiliation(s)
- Peter Funch-Jensen
- Surgical Gastroenterological Department L, Aarhus Sygehus, Aarhus University Hospital, DK-8000 Aarhus C, Denmark.
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Abstract
Cholecystokinin (CCK) is a peptide hormone which is found both in the gastrointestinal tract throughout the human small intestine and nerves in the myenteric plexus of the enteric nervous system and in the central nervous system. This dual location constitutes the anatomical basis for this in functions as a hormone and a neurotransmitter implicated in the regulation of both systems. CCK regulates not only motor functions in the gastrointestinal tract like lower oesophageal sphincter relaxation, gastric secretion and emptying, gall bladder contractility and bile secretion into the duodenum, intestinal and colonic motility, but also sensory functions and plays a role in the regulation of food intake. These effects are mediated through selective receptors CCK1 and CCK2. Over the last few years, research has focused on understanding the role of CCK, its receptors with antagonists at the biological, pharmacological, clinical and therapeutic level. As far as the CCK1 antagonists is concerned, important inroads have been made in the potential role of these antagonists in the treatment of GERD, IBS and pancreatitis. They have also shown encouraging results in sphincter of Oddi dysfunction and some gastrointestinal cancers. This review focuses on the recent ad vances of the biological role of CCK and their CCK1 antagonists: their current basic and clinical status in gastroenterology, with particular emphasis on the potential therapeutic role of the CCK1 antagonists and future research directions.
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Affiliation(s)
- Shajan A S Peter
- Department of Gastroenterology, University Hospital, Basel, Switzerland
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Sahan-Firat S, Tiftik RN, Nacak M, Büyükafşar K. Rho kinase expression and its central role in ovine gallbladder contractions elicited by a variety of excitatory stimuli. Eur J Pharmacol 2005; 528:169-75. [PMID: 16324691 DOI: 10.1016/j.ejphar.2005.10.055] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2005] [Revised: 10/21/2005] [Accepted: 10/26/2005] [Indexed: 12/18/2022]
Abstract
Rho kinase has contractile activity, which induces Ca2+ sensitization in various cells. Several receptors are linked to the Rho/Rho-kinase pathway. Therefore, in this study we aimed to demonstrate the central importance of this novel pathway for diverse excitatory stimuli in the smooth muscle of the sheep gallbladder. Accordingly, the effects of a Rho kinase inhibitor, (+)-(R)-trans-4-(1-aminoethyl)-N-(4-pyridyl) cyclohexanecarboxamide dihydrochloride monohydrate (Y-27632, 10(-8)-3 x 10(-5) M), were investigated on cholecystokinin-8 (CCK-8, 10(-8) M), endothelin-1 (10(-8) M), carbachol (10(-6)-10(-5) M), 5-hydroxytryptamine (5-HT, 10(-6)-10(-5) M), histamine (10(-6)-10(-5) M), phenylephrine (10(-5)-10(-4) M), neurokinin A (10(-7)-10(-6) M), electrical field stimulation (40 V, 0.5 ms, 2, 4, 8, 16, 32 Hz, 15 s, 3 min intervals) and potassium chloride (KCl, 25-50 mM)-induced contractions as well as spontaneous contractile activity. Electrical field stimulation evoked tetrodotoxin (3 x 10(-6) M)-sensitive reproducible contractions, which were inhibited by atropine (2 x 10(-6) M) and potentiated by eserine (5 x 10(-7) M). EFS-induced contraction was significantly inhibited by Y-27632 (10(-5) M). In addition, spontaneous contractile activity was suppressed in the presence of the compound (10(-6)-10(-5) M). This Rho kinase inhibitor also dramatically decreased the contractions elicited by 5-HT, neurokinin A and carbachol. KCl-induced contraction, which was not atropine-sensitive, was also conspicuously attenuated by Y-27632. Moreover, Y-27632 (10(-8)-3 x 10(-5) M) relaxed gallbladder strips that were contracted by histamine, endothelin-1, CCK-8 and phenylephrine in a concentration-dependent manner. pEC50 values for Y-27632 were 6.25+/-0.10, 5.79+/-0.12, 5.83+/-0.09 and 5.70+/-0.13 for the contraction elicited by histamine, CCK-8, endothelin-1 and phenylephrine, respectively. Furthermore, we also demonstrated Rho kinase protein expression (ROCK-1 and ROCK-2) by Western blot analysis. In conclusion, ROCK is expressed in the smooth muscle of the ovine gallbladder, and it has a central role in the contractile activity induced by diverse excitatory stimuli.
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Affiliation(s)
- Seyhan Sahan-Firat
- Department of Pharmacology Medical Faculty Mersin University Campus Yenişehir 33169 Mersin, Turkey
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Pálvölgyi A, Sári R, Németh J, Szabolcs A, Nagy I, Hegyi P, Lonovics J, Szilvássy Z. Interplay between nitric oxide and VIP in CCK-8-induced phasic contractile activity in the rabbit sphincter of Oddi. World J Gastroenterol 2005; 11:3264-3266. [PMID: 15929179 PMCID: PMC4316060 DOI: 10.3748/wjg.v11.i21.3264] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2004] [Revised: 06/18/2004] [Accepted: 07/27/2004] [Indexed: 02/06/2023] Open
Abstract
AIM The sphincter of Oddi (SO) plays an important role in delivery of bile into the duodenum. To establish whether vasoactive intestinal polypeptide (VIP) and nitric oxide (NO) were involved in phasic contractile activity of the rabbit SO stimulated by cholecystokinin-octapeptide (CCK-8). METHODS Isolated SO muscle rings were cleaned of fat and mounted horizontally on two small L-shaped hooks one of which was connected to a force transducer for the measurement of isometric tension. The experiments were carried out in a thermostatically controlled (37+/-0.2 degrees) organ bath (5 mL) containing Krebs solution. The organ fluid was gassed with 95% O(2) and 50 mL/L CO(2) to keep the pH at 7.40+/-0.05. Contractile responses to CCK-8 (1 micromol/L) were evaluated in the presence and absence of N(G)-nitro-L-arginine (LNNA), an inhibitor of NO synthase (100 micromol/L), and (p-chloro-D-Phe(6)-Leu(17))-VIP (VIPa, 30 micromol/L), a VIP receptor antagonist. RESULTS CCK-8 stimulated the phasic activity of the SO. NO synthase inhibition increased the frequency and amplitude of contractions with a slight increase in developed tension. Pre-incubation with VIPa also attenuated this CCK-8 effect. The combined application of LNNA and VIPa abolished the phasic activity of the muscle rings with a marked increase in tension in response to CCK-8. CONCLUSION VIP and NO together contribute to an increase in phasic activity of SO.
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Affiliation(s)
- Attila Pálvölgyi
- First Department of Medicine, University of Szeged, H-6720 Szeged, Hungary
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Mizushima T, Ochi K, Ichimura M, Kiura K, Harada H, Koide N. Pancreatic enzyme supplement improves dysmotility in chronic pancreatitis patients. J Gastroenterol Hepatol 2004; 19:1005-9. [PMID: 15304117 DOI: 10.1111/j.1440-1746.2004.03429.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Abstract
BACKGROUND AND AIMS Impaired gallbladder contraction and rapid gastric emptying in patients with chronic pancreatitis may be the result of depleted pancreatic exocrine function. The authors tested whether oral pancreatic enzymes can improve the dysmotility or not. METHODS Study subjects consisted of 15 patients with chronic pancreatitis and 18 healthy controls. The gastric emptying time and gallbladder contraction were studied. All patients were initially studied using a test meal without pancreatic enzymes, followed on separate days by a test meal with a single and a triple dose of pancreatic enzymes. Blood samples were taken before and 2 h after the test meal to determine the pancreatic polypeptide levels. RESULTS In patients with chronic pancreatitis, gallbladder contraction at 15 min after the meal was impaired. The gastric emptying time was faster and the ratio of pre- to postprandial pancreatic polypeptide levels was enhanced. A single dose and a triple dose of oral enzymes further improved the gastric emptying time and the pancreatic polypeptide ration, but did not improve the gallbladder contraction rate at 15 min. CONCLUSIONS It was demonstrated that the oral pancreatic enzymes improved the gastric dysmotility, confirming the previous findings that suggested the depleted pancreatic enzyme output caused the dysmotility.
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Affiliation(s)
- Takaaki Mizushima
- Department of Clinical Laboratory Medicine, Okayama University Medical School, Okayama, Japan.
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Kuo YI, Chiu JH, Lin JG, Hsieh CL, Wu CW. Chinese medicinal herbs Muh-Shiang Bin-Lang-Wan increases the motility of sphincter of Oddi in anesthetized rabbits through activation of M1 muscarinic receptors. Life Sci 2003; 74:533-42. [PMID: 14609730 DOI: 10.1016/j.lfs.2003.09.032] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
The sphincter of Oddi (SO) plays an important role in regulating the bile flow into the duodenum. This study was designed to investigate the effect of Chinese Medicinal Herbs Muh-Shiang-Bin-Lang-Wan (MSBLW) and their mechanism of action on regulating the motility of SO in rabbits. The activity of SO in anesthetized rabbits was measured by using a continuously perfused open-tip manometric method. The rabbits were administered with different doses of MSBLW through naso-gastric tubes. The SO motility before and after the administration of MSBLW were recorded, and analyzed with a computer equipped with an off line analysis software. The results showed that the SO activity, in terms of tonic pressure and phasic contraction pressure, were significantly changed. A significant lower tonic pressure and a higher phasic contraction pressure were noticed 40-60 min after administration of MSBLW with a peak response at 0.5-1.0 gm range. The responses were blocked by pretreatment of muscarinic receptors (M1) antagonist, pirenzepine (10 mg/kg, orally). We conclude that MSBLW is effective in increasing the SO motility in rabbits through activation of M1 muscarinic receptors. However, potential application of MSBLW in the treatment of human biliary disorders needs further evaluation.
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Affiliation(s)
- Yung-ing Kuo
- Institute of Chinese Medicine Science, China Medical University, Taichung, Taiwan, ROC
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Martínez-Cuesta MA, Moreno L, Morillas J, Ponce J, Esplugues JV. Influence of cholecystitis state on pharmacological response to cholecystokinin of isolated human gallbladder with gallstones. Dig Dis Sci 2003; 48:898-905. [PMID: 12772786 DOI: 10.1023/a:1023091327412] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Abstract
We studied the influence of the inflammatory state of the gallbladder with gallstones on its response to cholecystokinin (CCK). Responses to CCK were evaluated in isolated human gallbladder strips incubated with pharmacological antagonists. Gallbladders from patients with gallstones were classified as having mild and severe chronic cholecystitis. Healthy gallbladders were collected from liver donors. In donor gallbladders, the CCK contraction was abolished with the CCK-A receptor antagonist, L-364718, and significantly reduced by indomethacin. In gallbladders with gallstones, only mild cholecystitis showed a decreased contraction to CCK. In gallbladders with gallstones, no involvement of prostaglandins in the CCK response was observed. In severe cholecystitis, CCK contractile effect was reduced by the serotonin receptor antagonist methysergide. In healthy gallbladder, the contraction provoked by CCK is mediated by CCK-A receptors and modulated by prostaglandins. The presence of gallstones in the gallbladder is correlated with a loss of prostaglandins-modulated CCK contraction. However, the excessive release of serotonin in advanced cholecystitis normalizes the contraction to CCK, suggesting that the state of cholecystitis affects the pool of inflammatory mediators responsible for gallbladder CCK-altered motility.
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Nabae T, Yokohata K, Otsuka T, Inoue K, Yamaguchi K, Chijiiwa K, Tanaka M. Effect of truncal vagotomy on sphincter of oddi cyclic motility in conscious dogs. Ann Surg 2002; 236:98-104. [PMID: 12131091 PMCID: PMC1422554 DOI: 10.1097/00000658-200207000-00015] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
OBJECTIVE To evaluate the effects of truncal vagotomy at the diaphragmatic level on the sphincter of Oddi (SO) motility. SUMMARY BACKGROUND DATA Cholelithiasis is a well-known late complication after gastrectomy and/or vagotomy. The mechanism of gallstone formation is only partly understood, and few studies address the effects of vagotomy on SO cyclic motility in conscious subjects. METHODS In conscious dogs, SO motility was recorded by retrograde infusion manometry through a duodenal cannula before and after bilateral truncal vagotomy at the diaphragmatic level. Effects of cholecystokinin-octapeptide and feeding were also evaluated before and after vagotomy. RESULTS SO cyclic motility and the gastroduodenal migrating motor complex continued to occur during postvagotomy fasting. Intermittent inhibitions of the SO and duodenal contractions disappeared during phase 3 of the migrating motor complex. SO basal pressure significantly decreased, whereas the amplitude significantly increased. Cholecystokinin-octapeptide inhibited SO contractions before and after vagotomy. The amplitude of SO contractions increased and their frequency decreased after feeding; however, these effects disappeared after vagotomy. CONCLUSIONS SO cyclic motility and the effects of feeding change after truncal vagotomy at the diaphragmatic level. These facts may at least partly explain gallstone formation after gastric surgery and/or vagotomy.
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Affiliation(s)
- Toshinaga Nabae
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
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Abstract
Muscular contraction of the gall-bladder is the primary determinant of bile delivery into the duodenum. Where bile goes following its secretion by the liver depends upon a co-ordinated series of pressure interrelations between the hepatic secretory pressure at the entrance to the biliary system, a low pressure conduit, and the pressure differences between the gall-bladder, cystic duct and sphincter of Oddi. During fasting, the relatively higher tone in the sphincter of Oddi fosters the entry of bile into the gall-bladder. The gall-bladder accommodates this influx without an increase in intravesicular pressure through its compliance or distensibility, which consists of active muscle relaxation and passive fibroelastic components. The concentrating function of the gall-bladder keeps the volume small. Once about every 120 min during the interdigestive period, gall-bladder emptying occurs coincident with intense duodenal contractions; all part of the migratory myoelectric complex. This helps maintain the enterohepatic circulation of bile salts. Motilin, which mediates these events during fasting, acts by stimulating intrinsic cholinergic nerves. Cholecystokinin is the major determinant of gallbladder emptying with eating. Cholecystokinin acts through pre-ganglionic cholinergic nerves, to initiate gall-bladder contraction. Agonists like cholecystokinin and acetylcholine cause contraction of gall-bladder smooth muscle through signal transduction, which increases intracellular calcium levels and so initiates the contractile machinery. Cholecystokinin also acts on the sphincter of Oddi via pre-ganglionic cholinergic nerves to release vasoactive intestinal polypeptide and nitric oxide, and so lower tone. These events are co-ordinated with motility and secretory events in the upper gastrointestinal tract, delivering bile at appropriate times into the duodenum.
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Affiliation(s)
- E A Shaffer
- Department of Medicine, University of Calgary, Faculty of Medicine, Foothills Medical Center, Alberta, Canada.
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Kennedy AL, Saccone GT, Mawe GM. Direct neuronal interactions between the duodenum and the sphincter of Oddi. Curr Gastroenterol Rep 2000; 2:104-11. [PMID: 10981011 DOI: 10.1007/s11894-000-0093-x] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
The sphincter of Oddi (SO) is a complex structure that must function in coordination with the motor activities of the gallbladder and the duodenum. It is now clear that a neural circuit exists between the duodenum and the SO, and it is likely that this network is largely responsible for the regulation of SO motility. Recent studies have demonstrated that this circuit provides excitatory cholinergic input to SO ganglia that can be activated by electrical stimulation of the duodenal mucosa, distention of the duodenum, and increased motor activity of the duodenum.
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Affiliation(s)
- A L Kennedy
- Department of Biological Sciences, Bridgewater State College, Bridgewater, MA, USA
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Kapraali M, Johansson O, Uribe A. Endogenous prostaglandins are physiological regulators of endocrine cells in the gastroduodenal mucosa of the rat. REGULATORY PEPTIDES 1999; 83:105-16. [PMID: 10511464 DOI: 10.1016/s0167-0115(99)00053-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/17/2022]
Abstract
BACKGROUND/AIM To investigate whether endogenous prostaglandins participate in the regulation of the gastrointestinal endocrine cell system. METHODS Sprague-Dawley rats were treated with 1 mg/kg indomethacin subcutaneously or indomethacin subcutaneously and 500 microg/kg oral prostaglandin E2 or solvents for 2 months. Endocrine cells were visualized by using immunohistochemistry and by the Sevier-Munger silver stain on specimens from the gastroduodenal mucosa, and their total volume was estimated, using standard stereological methods. Plasma and gastrointestinal tissue concentrations of regulatory peptides were analyzed by radioimmunoassay. RESULTS Fundic mucosa. The total volume of cells stained with the Sevier-Munger silver stain (enterochromaffin-like) was increased by indomethacin, but reduced by the administration of prostaglandin E2 (P < 0.05 vs. indomethacin). Indomethacin increased the total volume of somatostatin-immunoreactive. Similarly, rats given indomethacin and prostaglandin E2 had higher values than controls. Indomethacin increased the tissue concentration of somatostatin in the gastric fundus whereas prostaglandin E2 prevented such changes (P < 0.05 vs. indomethacin). Antral mucosa. The total volume of serotonin-immunoreactive cells was reduced by indomethacin, but increased by prostaglandin E2 (P < 0.05 vs. controls and indomethacin, respectively). Duodenal mucosa. The total volume of somatostatin-immunoreactive cells was reduced in the rats given indomethacin and prostaglandin E2 (P < 0.05 vs. controls and indomethacin). Indomethacin reduced and simultaneous administration of prostaglandin E2 increased the total volume of CCK-immunoreactive cells (P < 0.05 vs. controls and indomethacin). Indomethacin reduced the total volume of serotonin-immunoreactive cells whereas the simultaneous administration of PGE2 comparatively increased their total volumes (P < 0.05 vs. indomethacin), although they were still lower than the control values. The total volume of GIP-immunoreactive cells was slightly increased in the rats given both indomethacin and indomethacin + prostaglandin E2. The tissue concentration of somatostatin in the duodenum was reduced in rats given indometacin and prostaglandin E2 (P < 0.05 vs. controls and indomethacin). CONCLUSION Endogenous prostaglandins, particularly prostaglandin E2, regulate CCK-, enterochromaffin-like-, somatostatin-, GIP- and enterochromaffin cells in the gastroduodenal mucosa of the rat.
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Affiliation(s)
- M Kapraali
- Division of Internal Medicine, Danderyd Hospital, Karolinska Institute, Sweden
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Lonovics J, Madácsy L, Szepes A, Szilvássy Z, Velösy B, Varró V. Humoral mechanisms and clinical aspects of biliary tract motility. SCANDINAVIAN JOURNAL OF GASTROENTEROLOGY. SUPPLEMENT 1998; 228:73-89. [PMID: 9867117 DOI: 10.1080/003655298750026606] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/09/2023]
Abstract
This review is intended to summarize current information on neurohumoral regulation of the gallbladder and sphincter of Oddi motility under both physiological and pathological circumstances with emphasis on Hungarian contributions to today's knowledge. The mechanism of action of neurohumoral agents that interact on these segments of the biliary tract, and the explored details of the stimulation-contraction/relaxation coupling process of these substances, will be discussed. A modified classification of biliary tract motility disorders with new diagnostic and therapeutic approaches will also be provided. This information will aid understanding of the pathogenesis of motor disorders of the gallbladder and sphincter of Oddi, and will indicate possibilities for pharmacological exploitation in the treatment of diseases resulting from biliary tract motility abnormalities.
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Affiliation(s)
- J Lonovics
- First Dept. of Medicine, Albert Szent-Györgyi Medical University, Szeged, Hungary
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Hillsley K, Mawe GM. 5-HT is present in nerves of guinea pig sphincter of Oddi and depolarizes sphincter of Oddi neurons. THE AMERICAN JOURNAL OF PHYSIOLOGY 1998; 275:G1018-27. [PMID: 9815032 DOI: 10.1152/ajpgi.1998.275.5.g1018] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/09/2023]
Abstract
This study involved immunohistochemistry and intracellular electrophysiology to investigate serotonergic neurotransmission in the sphincter of Oddi (SO). 5-Hydroxytryptamine (HT)-positive neurons (14 cells/preparation) and nerve fibers were observed in the ganglionated plexus. Serotonergic nerve fibers, which persisted under 2- to 6-day organ culture, were densely distributed, with varicose endings encircling some SO neurons. When 5-HT was applied to SO neurons, it elicited three different responses: 1) a fast depolarization to 5-HT in 31 of 62 cells was mimicked by 2-methyl-5-HT and blocked by LY-278584 (1 microM); 2) a prolonged depolarization to 5-HT in 21 of 62 cells evoked an increase in input resistance and was attenuated by the 5-HT1P antagonist renzapride (1 microM) but not by the 5-HT4 antagonist SDZ-205557 (0.1-10 microM); and 3) an indirect depolarization blocked by TTX or atropine was observed in 32 of 62 cells. 5-HT superfusion elicited a dose-dependent monophasic depolarization (EC50 = 2 microM, n=14). In conclusion, 5-HT is present in nerves of the SO and elicits both 5-HT3 and 5-HT1P receptor-mediated depolarizations, supporting the concept that 5-HT plays a role in SO regulation.
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Affiliation(s)
- K Hillsley
- Department of Anatomy and Neurobiology, University of Vermont, Burlington, Vermont 05405, USA
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Huang J, Padbury RT, Schloithe AC, Cox MR, Simula ME, Harvey JR, Baker RA, Toouli J, Saccone GT. Somatostatin stimulates the brush-tailed possum sphincter of Oddi in vitro and in vivo. Gastroenterology 1998; 115:672-9. [PMID: 9721164 DOI: 10.1016/s0016-5085(98)70146-5] [Citation(s) in RCA: 19] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/02/2022]
Abstract
BACKGROUND & AIMS Somatostatin, a neuropeptide and hormone, is found in the biliary tract of several species. The aim of this study was to map the distribution of somatostatin-like immunoreactive nerve fibers in the extrahepatic biliary tract of the Australian possum and to determine the pharmacological effects of somatostatin 1-14 on sphincter of Oddi activity in vitro and in vivo. METHODS Tissue was harvested for immunohistochemistry and sphincter of Oddi for circular or longitudinal muscle contractility. In anesthetized possums, sphincter of Oddi motility was measured by manometry, and transsphincteric flow was measured gravimetrically. RESULTS Somatostatin immunoreactivity was evident in gallbladder ganglia nerve cell bodies and in nerve fibers of the common bile duct and sphincter of Oddi. Somatostatin 1-14 increased circular and longitudinal muscle contraction amplitude 3-4-fold (P < 0.05), but only the longitudinal muscle contraction amplitude was tetrodotoxin sensitive. Somatostatin 1-14 stimulated spontaneous sphincter of Oddi motility in a tetrodotoxin-insensitive manner, increasing basal pressure, contraction frequency, and amplitude 2-4-fold (P < 0.05) and reducing transsphincteric flow to 25% of control (P < 0.0001). CONCLUSIONS Somatostatin-like immunoreactivity is present in the extrahepatic biliary tree, and somatostatin 1-14 stimulates sphincter of Oddi smooth muscle and nerves. The major action is direct stimulation of sphincter of Oddi circular muscle, which reduces transsphincteric flow.
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Affiliation(s)
- J Huang
- Department of Surgery, Flinders University, Flinders Medical Centre, Bedford Park, South Australia, Australia
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Yu P, Chen Q, Xiao Z, Harnett K, Biancani P, Behar J. Signal transduction pathways mediating CCK-induced gallbladder muscle contraction. THE AMERICAN JOURNAL OF PHYSIOLOGY 1998; 275:G203-11. [PMID: 9688646 DOI: 10.1152/ajpgi.1998.275.2.g203] [Citation(s) in RCA: 25] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
The signal transduction that mediates CCK-induced contraction of gallbladder muscle was investigated in the cat. Contraction was measured by scanning micrometry in single muscle cells isolated enzymatically with collagenase. Production of D-myo-inositol 1,4, 5-trisphosphate (IP3) and sn-1,2-diacylglycerol (DAG) was quantitated using HPLC and TLC, respectively. Protein kinase C (PKC) activity was determined by measuring the phosphorylation of a specific substrate peptide from myelin basic protein, Ac-MBP-(4-14). CCK-induced contraction was blocked by incubation in strontium medium, pertussis toxin (PTx), and antibodies against Gialpha3 or betagamma-subunits but was not blocked by Ca2+-free medium or by antibodies against Gq/11alpha, Gialpha1-2, or Goalpha. The contraction induced by CCK was inhibited by the phospholipase C (PLC) inhibitor U-73122, anti-PLC-beta3 antibody, and the IP3 receptor antagonist heparin but was not inhibited by the the phospholipase D inhibitor propranolol or antibodies against PLC-beta1 or PLC-beta2. Western blot analysis of gallbladder muscle revealed the presence of PLC-beta2 and PLC-beta3 but not PLC-beta1. CCK caused a 94% increase in IP3 generation and an 86% increase in DAG generation. A low dose of CCK caused PKC translocation, and CCK-induced contraction was blocked by the PKC inhibitor H-7. A high dose of CCK, however, caused no PKC translocation, and its contraction was blocked by the calmodulin antagonist CGS9343B. In conclusion, CCK contracts cat gallbladder muscle by stimulating PTx-sensitive Gi 3 protein coupled with PLC-beta3, producing IP3 and DAG. Low doses activate PKC, whereas high doses activate calmodulin.
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Affiliation(s)
- P Yu
- Department of Medicine, Rhode Island Hospital, and Brown University School of Medicine, Providence, Rhode Island 02903, USA
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Hillsley K, Mawe GM. Correlation of electrophysiology, neurochemistry and axonal projections of guinea-pig sphincter of Oddi neurones. Neurogastroenterol Motil 1998; 10:235-44. [PMID: 9659667 DOI: 10.1046/j.1365-2982.1998.00101.x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Sphincter of Oddi (SO) ganglia are comprised of two main types of neurones based either on their electrical or neurochemical properties. This study investigated whether any correlation exists between the electrical and neurochemical properties of these cells. SO neurones were characterized electrically as either Tonic or Phasic cells, labelled with neurobiotin, fixed, and processed for beta-nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-DA) staining and choline acetyltransferase immuno-reactivity to identify whether electrically characterized neurones were nitrergic or cholinergic. A total of 119 cells were analysed in this manner; 45% of cells were Tonic and 37% were Phasic. An equivalent number of Tonic (58.1%, 18/31) and Phasic cells (60%, 21/35) were choline acetyltransferase (ChAT) positive. Three of 34 Phasic cells were NADPH-DA positive, whereas 11/33 Tonic cells were NADPH-DA positive. In none of the preparations was ChAT immunoreactivity and NADPH-DA reactivity ever observed in the same neurone. Calretinin immunoreactivity was present in a subpopulation of both Tonic and Phasic neurones. No correlation was observed between the direction of axon projections and the electrophysiological or neurochemical properties of the cell. These results suggest that there is a lack of correlation between the electrical properties and the neurochemical content of SO neurones. Various explanations for these findings are discussed.
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Affiliation(s)
- K Hillsley
- Department of Anatomy and Neurobiology, University of Vermont, Burlington 05405, USA
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Shima Y, Mori M, Harano M, Tsuge H, Tanaka N, Yamazato T. Nitric oxide mediates cerulein-induced relaxation of canine sphincter of Oddi. Dig Dis Sci 1998; 43:547-53. [PMID: 9539650 DOI: 10.1023/a:1018811124191] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
This study evaluates the hypothesis that cerulein relaxes the sphincter of Oddi (SO) via nitric oxide (NO). The spontaneous motility and the response to cerulein on the canine SO were recorded using a constant-perfusion technique. N(G)-L-arginine-methyl-ester (L-NAME) increased the spontaneous motility and dose-dependently reduced the cerulein-induced inhibitory response of the SO. After treatment with L-NAME at higher doses, cerulein induced an excitatory response. This effect was reversed by treatment with excess L-arginine. Similar results were obtained using cholecystokinin octapeptide in place of cerulein. In separate studies, cerulein generated increases in intracellular cAMP and cGMP levels in the SO. This indicates that the intracellular mechanism mediating cerulein-induced relaxation involves the production of cAMP and cGMP. On the other hand, treatment with L-NAME absorbed the increase in cAMP and cGMP levels by cerulein. These studies demonstrate that cerulein relaxes the canine SO mainly via NO, increasing intracellular cAMP and cGMP levels.
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Affiliation(s)
- Y Shima
- First Department of Surgery, Okayama University Medical School, Japan
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Boeckxstaens GE, Pelckmans PA. Nitric oxide and the non-adrenergic non-cholinergic neurotransmission. COMPARATIVE BIOCHEMISTRY AND PHYSIOLOGY. PART A, PHYSIOLOGY 1997; 118:925-37. [PMID: 9505411 DOI: 10.1016/s0300-9629(97)00022-4] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
In the early 1960s, the first evidence was reported demonstrating neurally mediated responses in the presence of adrenergic and cholinergic antagonists, leading to the introduction of the concept of non-adrenergic non-cholinergic neurotransmission. The inhibitory component of this part of the autonomic nervous system has been illustrated in numerous organ systems mediating a wide range of physiological events. Since the discovery of these nerves, several substances have been proposed as putative neurotransmitter, with ATP and vasoactive intestinal polypeptide as main candidates. Finally, the ongoing research on the nature of the substance released by these nerves has generated the nitrergic theory proposing nitric oxide as putative neurotransmitter. By now, increasing evidence is reported to support the idea that inhibitory neurons release more neurotransmitters, interacting with each other at pre- and/or postsynaptic levels.
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Affiliation(s)
- G E Boeckxstaens
- Division of Gastroenterology, Academic Medical Center, Amsterdam, The Netherlands
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39
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Mawe GM, Talmage EK, Cornbrooks EB, Gokin AP, Zhang L, Jennings LJ. Innervation of the gallbladder: structure, neurochemical coding, and physiological properties of guinea pig gallbladder ganglia. Microsc Res Tech 1997; 39:1-13. [PMID: 9329015 DOI: 10.1002/(sici)1097-0029(19971001)39:1<1::aid-jemt1>3.0.co;2-r] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
The muscle and epithelial tissues of the gallbladder are regulated by a ganglionated plexus that lies within the wall of the organ. Although these ganglia are derived from the same set of precursor neural crest cells that colonize the gut, they exhibit structural, neurochemical and physiological characteristics that are distinct from the myenteric and submucous plexuses of the enteric nervous system. Structurally, the ganglionated plexus of the guinea pig gallbladder is comprised of small clusters of neurons that are located in the outer wall of the organ, between the serosa and underlying smooth muscle. The ganglia are encapsulated by a shell of fibroblasts and a basal lamina, and are devoid of collagen. Gallbladder neurons are rather simple in structure, consisting of a soma, a few short dendritic processes and one or two long axons. Results reported here indicate that all gallbladder neurons are probably cholinergic since they all express immunoreactivity for choline acetyltransferase. The majority of these neurons also express substance P, neuropeptide Y, and somatostatin, and a small remaining population of neurons express vasoactive intestinal peptide (VIP) immunoreactivity and NADPH-diaphorase enzymatic activity. We report here that NADPH-diaphorase activity, nitric oxide synthase immunoreactivity, and VIP immunoreactivity are expressed by the same neurons in the gallbladder. Physiological studies indicate that the ganglia of the gallbladder are the site of action of the following neurohumoral inputs: 1) all neurons receive nicotinic input from vagal preganglionic fibers; 2) norepinephrine released from sympathetic postganglionic fibers acts presynaptically on vagal terminals within gallbladder ganglia to decrease the release of acetylcholine from vagal terminals; 3) substance P and calcitonin gene-related peptide, which are co-expressed in sensory fibers, cause prolonged depolarizations of gallbladder neurons that resemble slow EPSPs; and 4) cholecystokinin (CCK) acts presynaptically within gallbladder ganglia to increase the release of acetylcholine from vagal terminals. Results reported here indicate that hormonal CCK can readily access gallbladder ganglia, since there is no evidence for a blood-ganglionic barrier in the gallbladder. Taken together, these results indicate that gallbladder ganglia are not simple relay stations, but rather sites of complex modulatory interactions that ultimately influence the functions of muscle and epithelial cells in the organ.
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Affiliation(s)
- G M Mawe
- Department of Anatomy and Neurobiology, University of Vermont, Burlington 05405, USA.
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Luman W, Williams AJ, Pryde A, Smith GD, Nixon SJ, Heading RC, Palmer KR. Influence of cholecystectomy on sphincter of Oddi motility. Gut 1997; 41:371-4. [PMID: 9378394 PMCID: PMC1891491 DOI: 10.1136/gut.41.3.371] [Citation(s) in RCA: 47] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
BACKGROUND Gall bladder and sphincter of Oddi (SO) function are coordinated by hormonal and neuronal mechanisms. Nerve fibres pass between the gall bladder and the SO via the cystic duct. It is therefore possible that cholecystectomy may alter SO motility. AIM To investigate the effect of cholecystectomy on SO function. METHODS SO manometry was performed in five women (median age 52 years), a few days before and six months after laparoscopic cholecystectomy which was undertaken for uncomplicated cholelithiasis. Basal and post-cholecystokinin (CCK) SO motility were measured. RESULTS All patients were symptom free after laparoscopic cholecystectomy. Prior to surgery common bile duct pressure, and tonic and phasic SO motility were normal and phasic contractions were inhibited by intravenous CCK (1 Ivy Dog Unit/kg). Six months later, common bile duct pressure and baseline tonic and phasic activity were unchanged but CCK failed to suppress phasic activity. CONCLUSION Cholecystectomy, at least in the short term, suppresses the normal inhibitory effect of pharmacological doses of CCK on the SO. The mechanism of this effect is unknown but it could be due to SO denervation.
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Affiliation(s)
- W Luman
- Gastrointestinal Unit, Western General Hospital, Edinburgh, Scotland, UK
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41
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Talmage EK, Hillsley K, Kennedy AL, Mawe GM. Identification of the cholinergic neurons in guinea-pig sphincter of Oddi ganglia. JOURNAL OF THE AUTONOMIC NERVOUS SYSTEM 1997; 64:12-8. [PMID: 9188080 DOI: 10.1016/s0165-1838(97)00009-x] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
The muscular tone of the sphincter of Oddi (SO) can be up- or down-regulated by neurons that lie within ganglia in the wall of the tissue. Previous studies have demonstrated that neurons in the ganglia of the guinea-pig SO can be classified into two major populations, one of which expresses tachykinins and enkephalin and another which expresses nitric oxide synthase. Although results of previous pharmacological studies indicate that acetylcholine is released in the SO, the neurons that express this neurotransmitter have not previously been identified. This study was conducted to establish which neurons in the ganglia of the guinea-pig SO are cholinergic by examining the distribution of choline acetyltransferase (ChAT) immunoreactivity, since the enzyme, ChAT is necessary for acetylcholine synthesis. Choline acetyltransferase immunoreactivity was intense and widespread in the ganglionated plexus of the SO. ChAT-immunoreactive nerve fibers were present in ganglia, interganglionic fiber bundles and in the circular muscle layer. Neurons that were immunoreactive for ChAT comprised about 69% of the population and most of these neurons were also tachykinin-immunoreactive. Co-expression of ChAT and nitric oxide synthase was not observed in nerve cell bodies or nerve fibers. Data from this study support the concept that SO ganglia are largely made up of two populations of neurons, one excitatory and the other inhibitory, on the basis of their chemical coding. The excitatory neurons are cholinergic and co-express tachykinin and opiate peptides and the inhibitory neurons are ChAT-negative and express nitric oxide synthase.
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Affiliation(s)
- E K Talmage
- Department of Anatomy and Neurobiology, College of Medicine, University of Vermont, Burlington 05405, USA
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42
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Einarsson S, Davies PS, Talbot C. Effect of exogenous cholecystokinin on the discharge of the gallbladder and the secretion of trypsin and chymotrypsin from the pancreas of the Atlantic salmon, Salmo salar L. COMPARATIVE BIOCHEMISTRY AND PHYSIOLOGY. PART C, PHARMACOLOGY, TOXICOLOGY & ENDOCRINOLOGY 1997; 117:63-7. [PMID: 9185328 DOI: 10.1016/s0742-8413(96)00226-5] [Citation(s) in RCA: 23] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
The humoral control of release of the proteases trypsin and chymotrypsin was investigated in the Atlantic salmon (Salmo salar L.). Intraperitoneal injection of a purified preparation of the peptide cholecystokinin (CCK) from pig into starved fish produces a dose-dependent release of both enzymes from the pyloric caeca/pancreas tissues which accumulate in the intestinal contents (digesta). It also induces release of the contents of the gallbladder. Isolated preparations of pyloric caeca/pancreas when incubated with CCK release trypsin and chymotrypsin. It is concluded that while a possible role for a neuronal component to the control and regulation of these enzymes cannot be ruled out, humoral control by a CCK-like peptide has been established. The fact that a mammalian-derived extract of CCK induces this response in fish indicates an early evolution and subsequent conservation of this control mechanism in the vertebrates.
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Affiliation(s)
- S Einarsson
- Department of Zoophysiology, Zoological Institute, Göteborgs University, Sweden
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43
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Schneider H, Sänger P, Hanisch E. In vitro effects of cholecystokinin fragments on human gallbladders. Evidence for an altered CCK-receptor structure in a subgroup of patients with gallstones. J Hepatol 1997; 26:1063-8. [PMID: 9186837 DOI: 10.1016/s0168-8278(97)80115-8] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND/AIM This study addresses cholecystokinin (CCK)-receptor alterations in stone-diseased and stone-free human gallbladders using different CCK-fragments. METHODS Serosa-free muscle strips were mounted in a modified Krebs-Henseleit-solution of 37 degrees C and aerated with carbogen. The following concentrations of CCK-fragments (CCK 26-33, N-Acetyl CCK 27-33 sulf., CCK 26-29 sulf., CCK 25-33 sulf.) were achieved: 0.1 nmol, 0.5 nmol, 2 nmol, 10 nmol, 100 nmol. RESULTS Stone-diseased gallbladders were classified into two groups based on their in vitro reaction to CCK 26-33 (CCK-octapeptide). Muscle strips not contracting below 10 nmol were assigned to the subcontractor group. Histologically scarification, necrosis and signs of severe inflammation of the mucosa were seen in 76.9% of this group. Those starting contractions at 0.1 nmol (like the control group) were called the contractor group. This group had a shallow mucosa and mild inflammatory signs in 54.5%. The sub-contractor group showed higher spontaneous phasic activity at lower tonic activity than the contractor and control groups. In the sub-contractor group CCK 27-33 caused several times higher contractions than all other fragments. A maximal contraction level in the contractor and control groups was reached by CCK 25-33. CONCLUSIONS This striking effect of CCK 27-33 in the sub-contractor group favors the view of CCK-receptor structural alteration in a subgroup of patients with cholecystolithiasis.
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Affiliation(s)
- H Schneider
- Department of General Surgery, Johann Wolfgang Goethe-University, Frankfurt/Main, Germany
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Machino H, Kobayashi H, Hayashi K, Tawara Y, Ito M, Kishimoto S. Nitric oxide is involved in the inhibitory action of cholecystokinin octapeptide (CCK-OP) on proximal colonic motility. REGULATORY PEPTIDES 1997; 69:47-52. [PMID: 9163582 DOI: 10.1016/s0167-0115(97)02128-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
To determine whether nitric oxide (NO) is a possible mediator in the inhibitory action of CCK-octapeptide (CCK-OP) on circular muscle contractions of the rat proximal colon, contractile activities of the circular muscle were recorded in the proximal colon of unrestrained conscious rats in the fasting state using a miniature strain gauge force transducer and an implantable telemetry system. Regular and rhythmic phasic contractions were observed during the fasted condition, similar to the myoelectric migrating complex seen in intestinal contractions of the fasting dog. These phasic contractions were almost completely inhibited after intraperitoneal (i.p.) administration of CCK-OP at a dose of 15 microg/kg body weight. N(omega)-nitro-arginine, methyl ester (L-NAME), at doses of 20 and 200 mg/kg i.p. administered prior to i.p. injection of CCK-OP, prevented the inhibitory action on the fasting phasic contractions. The degree of prevention was dose-dependent. 100 mg/kg body weight i.p. injection of L-arginine inhibited the circular muscle contractions. The same dose of D-arginine had no action on contractions of the circular muscle of the proximal colon in the fasted rat. From these data, we conclude that NO is one possible mediator in the inhibitory mechanism of CCK-OP on smooth muscle motor activity of the rat proximal colon in vivo.
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Affiliation(s)
- H Machino
- First Department of Internal Medicine, Hiroshima University School of Medicine, Minami-ku, Japan
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Krishnamurthy S, Krishnamurthy GT. Cholecystokinin and morphine pharmacological intervention during 99mTc-HIDA cholescintigraphy: a rational approach. Semin Nucl Med 1996; 26:16-24. [PMID: 8623048 DOI: 10.1016/s0001-2998(96)80013-4] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Pharmacological intervention with either cholecystokinin-8 (CCK-8) or morphine during 99mTc- hepatoiminodiacetic acid (HIDA) cholescintigraphy is required primarily for the assessment of the diseases affecting the gallbladder, the common bile duct, or the sphincter of Oddi. For imaging, the patient should be prepared by an overnight fast, or with 4 hours of minimum fast. Pre-emptying with CCK-8 is probably undesirable and should either be avoided or one should wait for at least 4 hours after CCK-8 to begin the 99mTc-HIDA study to achieve higher specificity of the test for acute cholecystitis. When he gallbladder is not observed by 60 mins in a clinical setting of acute cholecystitis, a dose of 0.04 mg/kg of morphine is administered intravenously and imaging continued for an additional 30 mins. Nonvisualization of the gallbladder by 90 mins with morphine in an appropriate clinical setting is diagnostic for acute cholecystitis. When the gallbladder is not observed by 60 min but is seen with morphine administered after 60 mins, a positive diagnosis of abnormal gallbladder function can be made. When the gallbladder is observed in a clinical setting of biliary pain or chronic calculous or acalculous cholecystitis, CCK-8 at a dose rate of 3.3 ng/kg/min is infused intravenously for 3 mins (10 ng/kg/3 min) for the measurement of the ejection fraction. An ejection fraction value of less than 35% is indicative of calculous or acalculous chronic cholecystitis. The gallbladder emptying is directly related to the total number of cholecystokinin receptors in the smooth muscle. The ejection fraction can be controlled to any desired level simply by controlling the dose rate or the duration of infusion of CCK-8. Morphine and other opiate metabolites circulate for many hours in blood and act on the sphincter of Oddi and decrease the gallbladder ejection fraction. Careful drug history, especially that of opiates, is very critical in all subjects with a low ejection fraction before assigning an abnormality to the gallbladder motor function.
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Affiliation(s)
- S Krishnamurthy
- Nuclear Medicine Department, Tuality Community Hospital, Hillsboro, OR, USA
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46
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47
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Jenkins SA, Berein A. Review article: the relative effectiveness of somatostatin and octreotide therapy in pancreatic disease. Aliment Pharmacol Ther 1995; 9:349-61. [PMID: 8527611 DOI: 10.1111/j.1365-2036.1995.tb00393.x] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Somatostatin and octreotide inhibit basal and stimulated pancreatic secretion, stimulate reticuloendothelial system activity, modulate the cytokine cascade and are cytoprotective with respect to the pancreas. These effects of somatostatin and octreotide suggest that both drugs may be useful either in the treatment of pancreatic disorders, or in preventing acute pancreatitis following procedures on the pancreas. In recent years it has become clear that somatostatin is a useful and effective therapy for severe acute pancreatitis and in preventing complications following endoscopic retrograde cholangiopancreatography (ERCP), whereas octreotide has no beneficial effect and may be deleterious in both these indications. The differences in the therapeutic efficacy of somatostatin and octreotide in acute pancreatitis and ERCP appears to be related to their differential effects on sphincter of Oddi motility--the native hormone relaxing, and the analogue increasing, its contractility. Consequently, any beneficial effects of octreotide in both acute pancreatitis and ERCP are offset by the increased contractility of the sphincter of Oddi, which results in retention of activated enzymes within the pancreas and further autodigestion of the gland. Somatostatin and octreotide are equally effective in promoting the closure of pancreatic fistulae. However, the time to closure after commencement of therapy is much more variable and longer in patients treated with subcutaneous octreotide than those receiving intravenous somatostatin, possibly as a result of fluctuations in pancreatic enzyme secretion between consecutive administrations of the hormone. Furthermore, the initial potent inhibitory effect of octreotide on pancreatic secretion is lost after 7 days of continuous subcutaneous administration. Therefore, in terms of cost-effectiveness, somatostatin would appear to be the treatment of choice for pancreatic fistulae. Octreotide markedly reduces the complication rates after elective pancreatic surgery. It remains to be established whether somatostatin is as effective as octreotide in this indication.
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Affiliation(s)
- S A Jenkins
- Department of Surgery, Royal Liverpool University Hospital, Vienna, Austria
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48
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Viceconte G, Micheletti A. Endoscopic manometry of the sphincter of Oddi: its usefulness for the diagnosis and treatment of benign papillary stenosis. Scand J Gastroenterol 1995; 30:797-803. [PMID: 7481549 DOI: 10.3109/00365529509096330] [Citation(s) in RCA: 19] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND Endoscopic manometry is considered useful to identify dysfunction of the sphincter of Oddi (SO) and to predict in which patients good results can be expected after endoscopic sphincterotomy, but this has not been definitively demonstrated. METHODS Endoscopic manometry of the SO was used in a group of 30 patients with benign papillary stenosis (BPS), in comparison with 30 control subjects. During endoscopic manometry an intravenous bolus of cholecystokinin octapeptide was given to 12 patients and to 10 controls. In 24 BPS patients endoscopic sphincterotomy was performed. RESULTS No significant differences were observed between controls and patients with regard to median values of SO basal (20 and 21.5 mmHg) and peak pressure (123 and 126 mmHg), wave amplitude (100 mmHg), frequency (4 waves/min), and propagation of the common bile duct/duodenum gradient (12.5 and 12.1 mmHg). In two BPS patients a paradoxic response to CCK-OP was observed. Endoscopic sphincterotomy, performed in 24 BPS patients (17 with SO basal pressure less than 40 mmHg and 7 with more than 40 mmHg), gave good results in 23, without any complication. No differences were observed in the results of the endoscopic sphincterotomy among patients with basal pressure more than 40 mmHg and those with less than 40 mmHg. CONCLUSIONS On the basis of this study, manometric data do not seem helpful for diagnosis of BPS or to discriminate which patients can be treated with endoscopic sphincterotomy.
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Affiliation(s)
- G Viceconte
- IIIrd Surgical Clinic, La Sapienza University, Rome, Italy
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49
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Wells DG, Talmage EK, Mawe GM. Immunohistochemical identification of neurons in ganglia of the guinea pig sphincter of Oddi. J Comp Neurol 1995; 352:106-16. [PMID: 7536219 DOI: 10.1002/cne.903520108] [Citation(s) in RCA: 19] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
The sphincter of Oddi is a smooth muscle sphincter that regulates the flow of bile into the duodenum. To identify potential chemical coding in sphincter of Oddi neurons, immunohistochemistry and histochemistry were employed to assay for putative neurotransmitters and related synthetic enzymes in wholemount preparations, with and without colchicine treatment. Immunoreactivities for enkephalin-endorphin (ENK-END), substance P (SP), nitric oxide synthase, vasoactive intestinal peptide (VIP), neuropeptide Y (NPY), and calcitonin gene-related peptide (CGRP) were demonstrated within the ganglionated plexus. Roughly half of the neurons in the sphincter of Oddi expressed immunoreactivity for both SP and ENK-END, but not for nitric oxide synthase. About 25% of the neurons expressed nitric oxide synthase immunoreactivity as well as NADPH-diaphorase activity. This contingent of neurons was made up of two subgroups: one that expressed immunoreactivity for VIP, the other for NPY. Neurons that expressed CGRP immunoreactivity were sparse in sphincter of Oddi ganglia; however, many axons immunoreactive for both CGRP and SP were present in the ganglionated plexus. The CGRP/SP fibers are probably visceral afferents that may influence ganglionic output through axon reflex circuits. These results, along with studies of the actions of these neuroactive compounds on sphincter tone, support the view that ganglia of the sphincter of Oddi are largely comprised of excitatory (SP/ENK-END-immunoreactive) and inhibitory (nitric oxide synthase/VIP- or NPY-immunoreactive) neurons, and that sphincter of Oddi tone is controlled by the regulation of the outputs of these two groups of cells.
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Affiliation(s)
- D G Wells
- Department of Anatomy and Neurobiology, College of Medicine, University of Vermont, Burlington 05405
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50
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Abstract
The case of a 50-year-old man with abdominal pain and abnormal liver test results is described. Endoscopic retrograde cholangiopancreatography with manometric studies showed biliary dilatation, poor ductal drainage, and sphincter of Oddi dysfunction. Clinical and radiographic clues suggested the possibility of an ampullary lesion; a small ampullary adenoma was detected after endoscopic sphincterotomy, and ampullary carcinoma was found in the operative specimen. Malignancy can cause sphincter dysfunction not only in the esophagus (as pseudoachalasia) but in the ampulla of Vater as well.
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Affiliation(s)
- M Topazian
- Department of Medicine, Yale University School of Medicine, New Haven, Connecticut
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