Effects of selective K+-channel agonists and antagonists on myoelectrical activity of a locus of the small bowel

Effects of Ca2+-activated K+ and voltage-activated K+-channel agonists and antagonists on the myoelectrical and contractile activity of a locus of the small bowel are simulated numerically. The model assumes that the electrical activity of smooth muscle syncytium is defined by kinetics of a mixture of L- and T-type Ca2+-channels, Ca2+-activated K+ and voltage-activated K+-channels, and leak Cl--channels, and that the smooth muscle syncytium of the locus is a null-dimensional contractile system. The results of modelling, both qualitatively and quantitatively, reproduce the effects of forskolin, lemakalim, phencyclidine, charybdotoxin and high concentration of external K+ ions, on gastrointestinal motility. This is confirmed by comparison with experimental observations conducted on the smooth muscle preparations of different species. © Springer-Verlag 1996

Stable isotope tracer studies for the measurement of equine gastrointestinal motility

Abdominal disorders are a major cause of morbidity and mortality in horses, and abnormal gastrointestinal motility may be a significant factor in the aetiopathogenesis of many equine colic syndromes. The understanding of such conditions is hampered by the lack of suitable noninvasive tests for the quantitative measurement of intestinal transit. The overall objective of this work was to investigate the potential value of stable 13C-isotope breath tests for the assessment of specific parameters of equine gastrointestinal motility. A new method developed for the collection of equine expiratory breath and measurement of its ratio was shown to have excellent repeatability. Assessment of peripheral blood tracer content was also performed and correlated significantly to that of concurrent breath samples. In the first study, the 13C-octanoic acid breath test (13C-OABT) was evaluated for the measurement of solid phase gastric emptying rate in 12 healthy horses by direct comparison with the predicate method of gastric scintigraphy. Having shown that the 13C-OABT was a reliable diagnostic procedure for use in healthy horses, a further study was performed against scintigraphy in subjects with atropine-induced gastroparesis (n = 8) to determine whether the test remained accurate when emptying rate was markedly prolonged. In study 3, the 13C-OABT was applied to measure the relative and dose-related effects of common sedative agents on solid phase gastric emptying in 8 horses. The study results may have clinical significance for case selection when these agents are used for purposes of sedation and/or analgesia. The 13C-bicarbonate and sodium 13C-acetate breath tests were investigated in study 4 for the assessment of equine liquid phase gastric emptying, and elucidation of the pattern of 13CO2 recovery from the body bicarbonate pool. The lactose 13C-ureide breath test (13C-LUBT) was investigated in study 5 for estimation of orocaecal transit time (OCTT), and concurrent comparison made to the hydrogen breath test (H2BT). In study 6 the induced 13C-LUBT was evaluated in vivo for the measurement of OCTT and a mean (+/- s.d.) time of 3.24 (+/- 0.65) h was gained. In order to examine the relationship between gastric emptying of solid ingesta, small bowel transit and its arrival in the caecum, a combined test was developed and applied in study 7, incorporating both 13C-OA and 13C-LU. Mathematical modelling of 13C recovery after ingestion of the dual test meal allowed calculation of small bowel half transit time, in addition to gastric and caecal parameters. Finally, minimised test protocols were developed for the 13C-OABT and 13C-LUBT in order to increase their clinical utility. The effects of decreasing the duration or frequency of breath collection on generation of intestinal transit parameters were assessed and linear regression models produced for each test based on the collection of 5 breath samples. Gastric t1/2, tlag and OCTT estimates from the reduced model and the full sampling protocols were highly correlated. However, in each case the reduced models were likely to underestimate these parameters when significantly prolonged, decreasing their sensitivity for the detection of delayed intestinal transit. The stable isotope breath tests offer a novel means of investigating features of intestinal motility and physiology in the horse and have potential value as both diagnostic modalities and humane research tools in this species. As the tests are non-invasive, simple to perform and do not require extensive equipment, they may be performed on site and the samples then submitted for isotopic analysis. Unlike other techniques for assessment of equine gastrointestinal motility, the stable isotope breath tests also provide an indirect measure of the transit rate of ingesta itself, which is directly relevant to the clinical situation. (Abstract shortened by ProQuest.)

Irritable Bowel Syndrome

Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder whose symptoms include abdominal pain associated with a change in stool form or frequency. The condition affects between 5% and 10% of otherwise healthy individuals in the community at any one point in time and, in most people, runs a relapsing and remitting course. The best described risk factor is acute enteric infection, but IBS is also more common in people with psychological co-morbidity, and in young adult females. The pathophysiology of IBS remains incompletely understood, but it is well established that there is disordered communication between the gut and the brain, leading to motility disturbances, visceral hypersensitivity, and altered central nervous system processing. Other less reproducible mechanisms may include genetic associations, alterations in gastrointestinal microbiota, and disturbances in mucosal and immune function. In most people the diagnosis can be made based on the clinical history, with limited, judicious, use of investigations, unless alarm symptoms such as weight loss or rectal bleeding are present, or there is a family history of inflammatory bowel disease or coeliac disease. Once the diagnosis is made, an empathetic approach is key, and can improve quality of life and symptoms, and reduce health care expenditure. The mainstays of treatment include patient education about the condition, dietary changes, soluble fibre, and antispasmodic drugs. Other treatments tend to be reserved for those with more severe symptoms; these include central neuromodulators, intestinal secretagogues, drugs acting on 5-hydroxytryptamine or opioid receptors, or minimally absorbed antibiotics (all of which are selected according to predominant bowel habit), and psychological therapies. The increased understanding of the pathophysiology of IBS in the last 10 years has led to a healthy pipeline of novel drugs in development

Bowel Disorders

Functional bowel disorders are highly prevalent disorders found worldwide. These disorders have the potential to affect all members of society, regardless of age, gender, race, creed, color or socioeconomic status. Improving our understanding of functional bowel disorders (FBD) is critical as they impose a negative economic impact to the global health care system in addition to reducing quality of life. Research in the basic and clinical sciences during the past decade has produced new information on the epidemiology, etiology, pathophysiology, diagnosis and treatment of FBDs. These important findings created a need to revise the Rome III criteria for FBDs, last published in 2006. This manuscript classifies the FBDs into five distinct categories: irritable bowel syndrome (IBS); functional constipation (FC); functional diarrhea (FDr); functional abdominal bloating/distention (FAB/D); and unspecified FBD (U-FBD). Also included in this article is a new sixth category, opioid induced constipation (OIC) which is distinct from the functional bowel disorders (FBDs). Each disorder will first be defined, followed by sections on epidemiology, rationale for changes from prior criteria, clinical evaluation, physiologic features, psychosocial features and treatment. It is the hope of this committee that this new information will assist both clinicians and researchers in the decade to com

Interplay between gut bacteria and Parkinson’s disease medication

Parkinson’s disease (PD) is a neurodegenerative disorder, which affects approximately 6 million individuals worldwide. The main pathologic feature observed in PD patients is the abnormal aggregation of protein and loss of dopaminergic neurons in the midbrain, resulting in motor deficits. Levodopa remains the “golden” standard treatment to restore the absence of dopamine in the brain. Although the start of levodopa treatment has an optimal efficacy, the progression of the disease causes a high variability in the efficacy of levodopa treatment among patients resulting in an unstable and unpredictable clinical response; motor-fluctuations. Besides motor deficits, PD patients also experience various non-motor symptoms such as gastrointestinal dysfunction. In this thesis, we showed that gut bacteria can contribute to the reduction of levodopa availability in the blood-circulation and that they can metabolize the unabsorbed residues of levodopa to various products that alter the gut motility. Furthermore, we showed that the most commonly used PD medications per se may affect the small intestinal motility, the main site of drug absorption, thereby altering the microbiota composition. Such events will potentially create a vicious cycle among the microbiota, PD medication, and gastrointestinal function, and urges for consideration of PD medication and gastrointestinal function when assessing alterations in the PD-associated microbiota. Finally, determining the clinical impact of gut bacteria on PD medication will help reduce the factors contributing to compromised levodopa bioavailability and the unwarranted side effects that result potentially in and from increased treatment regimen

Capsaicin - Sensitive Neural Afferentation and the Gastrointestinal Tract

The capsaicin, a component of paprika, has been used in the culinary practice of every day nutritional practice. This agent is known to cause a variety of actions in the body through activating capsaicin-sensitive afferent neurons. A recently launched book entitled, Capsaicin-Sensitive Neural Afferentation and the Gastrointestinal Tract: from Bench to Bedside, is attractive for several reasons. First, Prof. Mozsik, a chief editor of this book, is known internationally as an expert in capsaicin pharmacology. Since he has worked for many years as a head of internal medicine, taking care of patients with various GI diseases, he is able to make a correct interpretation of various findings obtained in basic researches to clinical events. Second, although there are many articles about capsaicin, they mostly deal with basic research and finding but do not include much about clinical finding. Third, this book encompassed review articles written by internationally accepted scientists leading the field of capsaicin research, who highlighted the current state of knowledge on pharmacology, physiology and clinical phathophysiology of capsaicin-sensitive afferent neurons, and discussed directions for future research. Overall, this book is for people who are interested in the capsaicin action in body

Slow transit constipation: clinical and aetiological studies.

PhDConstipation is the second most commonly self-reported gastrointestinal symptom. On the basis of anorectal physiological investigations and colonic transit studies, a subgroup of patients with several intractable symptoms, but without organic disease will be found to have slow transit constipation (STC). STC is a condition of gut dysmotility which predominantly affects young women, and may result in surgical intervention with variable, often unsatisfactory results. The aetiology remains elusive. New aetiological hypotheses for STC were examined following full clinical and pathophysiological characterisation of a large cohort of 130 patients referred to our institution over the last 10 years. Aspects of nerve and muscle dysfunction were studied. A new scoring system demonstrated some ability of multiple symptoms to discriminate STC from other forms of constipation. Detailed clinical and gastrointestinal physiological studies confirmed the heterogeneity of STC patients. Some significant physiological differences were detectable between clinically defined sub-groups of patients and refuted previous assumptions based on smaller numbers. Detailed neurophysiological studies, including quantitative peripheral sensory and autonomic testing, provided evidence of a small fibre neuropathy in a proportion of patients with STC. Mutational screening of some early-onset cases for a possible congenital pathogenetic mechanism, based on the observation that some STC patients had relatives with Hirschsprung's disease demonstrated that mutation of 2 important genes now implicated in this disorder were not a frequent cause of STC. Serum immunoprecipitation assays showed that anti-neuronal ion channel autoantibodies may have an as yet unrecognised role in the development of STC in a small proportion of acquired cases. An inclusion body myopathy was identifiable in colonic tissue of patients with STC, and this appeared to arise secondary to denervation. Further knowledge of the single or multiple pathogenetic mechanisms leading to this clinical condition may allow more rational or directed therapies aimed at the correction of the disease process or processes themselves