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Systemic hydration, plasma electrolytes, ingesta and fecal hydration and gastrointestinal passage of cobalt (after CoEDTA administration via nasogastric tube) in horses fed large grain meals or treated with enteral fluid therapy, IV fluid therapy and enteral laxatives were investigated. In the first study, 0.9% NaCl (10 L/h/8h) was administered slowly via a small-bore nasogastric tube or as 10 L boluses via a large-bore nasogastric tube to four normal horses. In the other studies, horses with a right dorsal colon fistula were used. To create the right dorsal colon fistula, a cannula with 5 cm internal diameter was implanted 2 to 6 weeks after a right dorsal colopexy had been created. Six horses with the right dorsal colostomy were alternately used to test three feeding regimes for 48 h: 1- hay free choice; 2- hay free choice plus 4.5 kg of sweet feed twice daily after a period of 5 days of adaptation; 3- sudden change from hay to hay plus sweet feed. Seven horses with the right dorsal colostomy were alternately used to test 6 experimental conditions while fasted for 24 h: 1- control (no treatment), 2- enteral MgSO4 (1 g/kg), 3- enteral Na2SO4 (1 g/kg), 4- IV lactated Ringer's solution (5 L/h/12 h), 5- enteral water (5 L/h/12 h), 6- enteral electrolyte solution (5 L/h/12 h). In the last study, four horses with the right dorsal colostomy were alternately treated with enteral electrolyte solution (10 L/h/6h) and enteral MgSO4 (1 g/kg) plus IV fluid therapy (10 L/h/6h). Despite the administration regimen, enteral administration of 0.9% NaCl produced diarrhea, hypernatremia and hyperchloremia. Colostomy allowed serial collection of large ingesta samples. Grain ingestion did not change PCV or plasma protein, but affected plasma electrolytes and produced dehydration of ingesta and formation of frothy ingesta. Fasting delayed gastrointestinal transit. Enteral fluid therapy was the most effective treatment in promoting ingesta hydration. Enteral water, MgSO4, Na2SO4, IV fluid therapy and enteral MgSO4 plus IV fluid therapy were either ineffective in promoting ingesta hydration or produced marked plasma electrolyte imbalance. These findings support the use of enteral fluid therapy in horses with gastrointestinal impaction. / Ph. D.

This thesis is concerned with the use of some of the newer techniques in a study of some of the effects of cigarette smoking on gastric secretion and gastric motility in normal subjects and in patients with active duodenal ulcers.

Hydrogen sulfide (H2S) is receiving increasing interest, as much as nitric oxide (NO) and carbon monoxide have received previously, to understand its physiological functions as it meets all the criteria to define as a third gasotransmitter. Endogenous synthesis from L-cysteine via cystathionine-γ-lyase (CSE) and cystathionine-β-synthase (CBS) and the function of H2S as an inhibitor of smooth muscle contraction in gastrointestinal tract are known. However, the loci of generation and action of H2S, and the mechanism of inhibition of contraction are unknown. Hence, my aims in the present study are to: i) identify the expression of enzymes in smooth muscle, ii) determine the effects of endogenously released and exogenously applied H2S on smooth muscle function; and iii) identify the targets and mechanism involved in mediating the effects of H2S using isolated smooth muscle cells from rabbit colon. I have identified the expression of CSE, but not CBS, in smooth muscle and demonstrated that L-cysteine (an activator of CSE) and NaHS (H2S donor): 1) inhibited carbachol-induced contraction in muscle strips and isolated muscle cells that was independent of KATP channels, a known S-sulfhydration target of H2S; 2) induced S-sulfhydration of small G protein, RhoA leading to inhibition of RhoA and Rho kinase activities, a key pathway in the sustained smooth muscle contraction; and 3) inhibited PDE5 activity leading to augmentation NO-induced cGMP formation and muscle relaxation. Sodium nitroprusside (an NO donor) induced an increase in H2S production via PKG-dependent phosphorylation and activation of CSE. We conclude that smooth muscle cells selectively express CSE, and endogenous generation of H2S via activation of CSE inhibits muscle contraction and augments muscle relaxation. Inhibition of contraction is mediated via S-sulfhydration of RhoA and suppression of RhoA/Rho kinase pathway. Augmentation of relaxation is mediated via inhibition of PDE5 activity and stimulation of cGMP/PKG pathway, which in addition initiates generation of H2S via PKG-mediated phosphorylation and activation of CSE. The findings are important in providing the underlying mechanisms involved in the regulation of smooth muscle function by H2S and could offer insights for the development of therapeutic agents that may act on smooth muscle in the gut to treat motility disorders.

Made available in DSpace on 2015-03-26T13:46:54Z (GMT). No. of bitstreams: 1 texto completo.pdf: 691613 bytes, checksum: 53e3adaea617739a5125fb5bc7242691 (MD5) Previous issue date: 2005-08-10 / Large colon (LC) impaction is the most commonly diagnosed disease causing colic in horses, however the complete ethyopathogenesis of this condition is still unknown.Changes produced by diet in the properties of ingesta not yet investigated may also be important contributing factors to impaction formation and to other gastrointestinal diseases. The aim of this study was: 1- to create a tube viscometer able to measure the viscosity of horse ingesta, 2- to assess the effects of grain intake on hydration, gas content, particulate matter content, density, viscosity, and pH of ingesta, 3- to assess the potential for impaction formation with large colon contents in an ex vivo model, 4- to testify a modification on surgical technique for right dorsal colon fistulation. Using a cross-over design, 4 horses with experimental fistulas in the right dorsal colon were alternately fed two diets: 1- exclusively free choice grass hay or 2- pelleted feed rich in hydrolazable carbohydrates plus free choice grass hay. The ingesta were dried at 80°C to determine the water content. The gas content was estimated by the difference in volume after centrifuging the ingesta sample. The amount of particulate mater was determined by flushing a 1 Kg fresh sample of ingesta in a sequence of sieves with 100 L of water and weighing the dry matter of the material retained at the sieves. Ingesta density was calculated by the formula: density = sample weight / sample volume. After measuring the force to move 1 kg of fresh ingesta within a tube viscometer and the force to penetrate a probe into the ingesta in a texture analyzer, the sample was tested for impaction formation with a funnel attached to the viscometer end, in order to increase the resistance to flow. The water content of ingesta as well as density were significantly decreased; gas content and viscosity were increased and pH and particulate matter was not altered, when grain was fed. Despite diet, impaction did not form with any of the fresh ingesta samples. After adjusting ingesta viscosity, impaction was formed in eight repetitions when only hay was fed. Only one impaction could be produced when hay and grain were fed in eight repetitions, even after adjusting ingesta viscosity. Ingesta dehydration produced by grain intake may be explained as the result of reduced water consumption or an increase in the absorption of water following the absorption of larger amounts of volatile fatty acids. Formation of foamy ingesta and the increase in gas content of ingesta is explained by an increase in microbial production of gas and substances that stabilizes the froth. The decreased density may be explained by the increased amount of gas trapped within the ingesta. The increase in viscosity may be explained by the reduced water content of ingesta. It is possible that these changes may affect the likelihood of impaction formation. Although it has been demonstrated that grain ingestion has the potential to increase the risk of colic by several mechanisms, the findings of the present study suggest that grain ingestion may actually have a protective effect for large colon impaction. / A compactação do cólon maior é a principal causa de cólica em eqüinos. No entanto, sua etiopatogenia ainda não é completamente conhecida. Alterações produzidas pela dieta em algumas propriedades da ingesta que ainda não foram estudadas podem contribuir para a formação das compactações e outras doenças gastrointestinais. Os objetivos desse estudo foram: 1- construir um viscosímetro de tubo capaz de medir a resistência viscosa da ingesta de eqüinos, 2- verificar os efeitos da ingestão de concentrado rico em grãos na hidratação, conteúdo de gás, conteúdo de partículas, densidade, viscosidade, pH e textura da ingesta, 3- verificar o potencial para formação de compactação da ingesta do cólon maior em um modelo ex vivo , 4- testar uma modificação da técnica cirúrgica pra criação de uma fístula no cólon dorsal direito . Em um delineamento tipo cross-over , quatro cavalos com fístulas experimentais no cólon dorsal direito foram alimentados alternadamente com duas dietas: 1- exclusivamente feno de gramínea e 2- feno de gramínea mais ração comercial peletizada . A ingesta foi desidratada a 80o C para determinação da hidratação. O conteúdo de gás foi estimado pela diferença no volume das amostras após centrifugação. O conteúdo de partículas foi determinado através da lavagem com 100 litros de água de 1 kg de ingesta fresca sobre uma seqüência de peneiras e pesando-se a matéria seca do material retido nas peneiras. A densidade foi calculada pela fórmula: peso da ingesta / volume da ingesta. Após a mensuração da força para mover 1 kg de ingesta em um viscosímetro de tubo e da força de penetração de uma sonda na ingesta em um texturômetro, a amostra foi testada para a formação de compactação, acoplando-se um funil redutor ao viscosímetro para aumentar a resistência ao fluxo. A hidratação e a densidade foram diminuídas, o conteúdo de gás e a viscosidade aumentadas e não houve diferença no pH e no conteúdo de partículas, quando os animais ingeriram ração à base de grãos. Independentes da dieta, não foram observadas compactações quando a ingesta fresca foi testada. No entanto, após o ajuste da viscosidade, foram formadas compactações em oito repetições quando a dieta era exclusivamente feno. Por outro lado, somente uma compactação foi observada em oito repetições quando os animais ingeriram ração à base de grãos. A desidratação da ingesta pode ser explicada pela menor ingestão ou pela absorção aumentada de água juntamente com ácidos graxos voláteis quando os animais receberam ração à base de grãos. A formação de espuma e o aumento na produção de gás na ingesta podem ser explicados pela fermentação microbiana aumentada e produção de substâncias estabilizadoras da espuma. A densidade diminuída foi devido a grande quantidade de gás incorporada à ingesta. O aumento da viscosidade pode ser explicado pela menor hidratação da ingesta. É possível que essas alterações influenciem o potencial da ingesta em formar compactações. Embora tenha sido demonstrado que o fornecimento de ração à base de grãos aumente o risco de cólica por vários mecanismos, os achados do presente trabalho sugerem um efeito protetor desse tipo de dieta contra a formação de compactação do cólon maior.

The stomach is a digestive organ in the gastrointestinal tract that regulates food intake and paces digestion of nutrients and fluids. The emptying and motility patterns of the stomach are crucial rate-determining processes in maintaining energy homeostasis in the body. Dysregulation of gastric functions often leads to distressing conditions such as gastroesophageal reflux diseases, functional dyspepsia, gastroparesis and obesity. Gastric disorders affect more than 60 million people in the US, producing significant medical and economic burden. These diseases are often chronic and greatly compromise quality of life. As the causes of these diseases remain largely unknown, effects of current pharmacological, dietary, or surgical treatments are often dismal. In this regard, neuromodulation of peripheral nerves emerges as a promising electroceutical therapy for remedying gastric disorders. However, therapeutic effects were shown to be modest, largely due to the inability to validate or calibrate the efficacy and stability of neuromodulation methods with appropriate physiological readouts. To address these problems, here I developed a non-invasive, repeatable online high-resolution magnetic resonance imaging protocol, empowered with advanced image processing algorithms, to track gastric emptying, antral motility, pyloric motility, intestinal filling and absorption in a rat model. The protocol can be used to guide tuning and optimization of stimulation parameters of neuromodulation without perturbing ongoing and spontaneous physiology. The proposed technology and findings are expected to pave the way for the use of gastric MRI to evaluate the efficacy of therapeutics in treating gastric disorders under both preclinical and clinical settings.