Non-steroidal anti-inflammatory drugs (NSAIDs) associate with zwitterionic phospholipids: insight into the mechanism and reversal of NSAID-induced gastrointestinal injury.

The molecular basis of the injurious actions of non-steroidal anti-inflammatory drugs (NSAIDs) on the gastrointestinal (GI) tract is only partly understood. In this study we have obtained evidence, employing both in vitro and in vivo systems, that five NSAIDs have the ability to form a chemical association with zwitterionic phospholipids. Since this same class of phospholipids line the luminal aspects of the mucus gel layer to provide it with non-wettable properties, this intermolecular association may be the mechanism by which NSAIDs attenuate the hydrophobic barrier properties of the upper GI tract. Preassociating a number of NSAIDs with exogenous zwitterionic phospholipids prevented this increase in surface wettability of the mucus gel layer and protected rats against the injurious GI side-effects of these drugs, while enhancing their lipid permeability, antipyretic and anti-inflammatory activity.

Hemorrhagic shock increases gut macromolecular permeability in the rat.

The effect of hemorrhagic shock on gut permeability to macromolecules was investigated using fluorescein isothiocyanate dextrans (4,300 or 73,100 daltons). These were given orally, then measured in systemic blood during hemorrhage (mean arterial pressure of 30 mmHg) and reperfusion; sham-shocked animals served as controls. Hemorrhage lasting 2 h resulted in a 5-fold increase in concentration of both tracers relative to that found in control groups. Reperfusion reduced these differences, with values approximately threefold greater than those of controls after 2 h. On a molar basis, the smaller molecule was more permeant than the larger one. This study provides evidence that hemorrhagic shock physically perturbs the normal barrier function of the mucosa, permitting very large substances in the gut lumen access to the circulation. It may further explain, at least in part, previous observations that hypovolemic shock results in bacterial translocation and endotoxemia.

Protective effect of a 21-aminosteroid against hemorrhage-induced ischemia-reperfusion injury in the rat stomach: role of lipid peroxidation.

We investigated the role that lipid peroxidation plays in a hemorrhage-induced ischemia-reperfusion model of gastric injury. Rats were pretreated with an inhibitor of this process, a 21-aminosteroid (U-74389G, 10 mg/kg), or an appropriate control solution intravenously 15 min prior to 20 min of ischemia, followed by 20 min of reperfusion. Results indicated that U-74389G pretreatment significantly attenuated gastric damage compared with corresponding control animals (19.8 vs. 176.8 mm2, p < .001). Enaldehyde levels (picomoles/mg protein), a biochemical index of lipid peroxidation, paralleled these injury findings (12 vs 960, p < .001). Histologically, U-74389G pretreatment almost completely prevented gastric injury compared to control stomachs. Additional studies revealed that lipid peroxidation preceded the formation of gastric damage, and injury occurred predominantly during reperfusion, because animals subjected to ischemia alone without reperfusion failed to develop appreciable injury or enhanced enaldehyde formation. Further, if U-74389G was given intravenously after ischemia, but prior to reperfusion, gastric injury and enaldehyde formation were similarly attenuated. Our findings are consistent with the hypothesis that lipid peroxidation likely plays an important role in hemorrhage-induced ischemia-reperfusion injury to the stomach.

Terephthalic acid: a dosimeter for the detection of hydroxyl radicals in vitro.

Hydroxylation reactions of aromatic compounds have been used to detect hydroxyl radicals produced by gamma irradiation and ultrasound. The present study investigated the suitability of terephthalic acid (THA) as a hydroxyl radical dosimeter for general use in biologically relevant reactions. Hydroxyl radicals were generated by: (1) irradiating THA with a 254 nm ultraviolet light; (2) irradiating with gamma rays from a cesium source; and (3) generating hydroxyl radicals with 1 mM H2O2 and 10 microM Cu+2. In each of the three experiments, a fluorescent product was generated which exhibited identical fluorescent excitation and emission spectra. THA is non-fluorescent, eliminating the problem of a high initial background. Because THA has four identical ring hydrogens, only one mono-hydroxylated isomer was formed. The hydrogen peroxide reaction was dependent on the presence of a metal and cupric ions were effective in enhancing the reaction. With a Cu+2 concentration of 10 microM, the reaction was linear between 0-30 mM H2O2. Catalase abolished the reaction at a concentration of 100 micrograms/ml and the effects could still be observed at 10 ng/ml, consistent with the very high rate at which catalase destroys hydrogen peroxide. Tertbutyl- hydroperoxide did not generate any fluorescence in this system which makes THA a very specific detector of hydroxyl radicals.

Monensin sodium and functional oil as additive in protein-energy supplement for pasture-fed heifers / Monensina sódica e óleo funcional como aditivo em suplemento protéico-energético para novilhas em pastejo

The use of functional oil as an additive is a potential alternative to replace inorganic antimicrobial agents. The objective of this study was to evaluate the effect of adding functional oil consisting of cashew and castor oil or monensin sodium to protein-energy supplement on the performance of 14-month-old Nellore x Red Angus heifers (initial mean body weight [BW] of 246 kg) raised on Tifton 85 pasture. The animals were randomly assigned to four treatments: 1) control (no supplementation); 2) addition of 2 g functional oil/animal/day, composed of 70% cashew oil and 30% castor oil; 3) addition of 4 g functional oil/animal/day, composed of 70% cashew oil and 30% castor oil, and 4) addition of 0.2 g monensin sodium/animal/day. The biomass availability and forage on offer were 5,940 kg dry matter/ha and 7.0 kg dry matter/100 kg BW/day, respectively. The average proportion of leaf blade, sheath plus stem and senescent material was 17.6%, 55.0% and 27.4%, respectively. The mean whole-plant contents of crude protein, neutral detergent fiber and in vitro dry matter digestibility were 8.5%, 72.3% and 42.7%, respectively...(AU)

A utilização de óleo funcional como aditivos é uma alternativa em potencial como substituto de agentes antimicrobianos não orgânicos. O trabalho teve como objetivo avaliar o efeito da adição de óleo funciomal, composto de óleos de caju e manona, e da monensina sódica em suplemento protéico-energético no desempenho de novilhas mestiças Nelore x Red Angus, com 14 meses de idade e peso corporal (PC) médio inicial de 246 kg, em pastejo de Tifton 85. Os animais foram distribuídos aleatoriamente em quatro tratamentos: 1) controle (sem suplementação); 2) adição de 2 g/animal/dia de óleo funcional, composto por 70% de óleo de caju e 30% de óleo de mamona, 3) adição de 4 g/animal/dia de óleo funciona, composto 70% de óleo de caju e 30% de óleo de mamona e 4) adição de 0,2 g/animal/dia de monensina sódica. A disponibilidade de biomassa forrageira e a oferta de forragem foram de 5.940 kg de matéria seca/ha e 7,0 kg de matéria seca/100 kg PC/dia. A proporção média de lâmina foliar, bainha mais colmo e material senescente foram de 17,6; 55,0 e 27,4%. Na planta inteira os teores médios de proteína bruta, fibra em detergente neutro e digestibilidade in vitro da matéria seca foram de 8,5%, 72,3% e 42,7%, respectivamente. Efeito significativo foi observado no ganho médio diário das novilhas que receberam monensina (0,576 g/dia) em relação as novilhas que não receberam o suplemento protéico-energético (0,290 g/dia). Já o suplemento com óleo funcional, composto de óleos de caju e mamona, proporcionaram ganhos de peso (0,426 g/dia) semelhantes (P>0,05) aos animais que receberam suplemento com monensina (0,576 g/dia)...(AU)

Monensin sodium and functional oil as additive in protein-energy supplement for pasture-fed heifers / Monensina sódica e óleo funcional como aditivo em suplemento protéico-energético para novilhas em pastejo

The use of functional oil as an additive is a potential alternative to replace inorganic antimicrobial agents. The objective of this study was to evaluate the effect of adding functional oil consisting of cashew and castor oil or monensin sodium to protein-energy supplement on the performance of 14-month-old Nellore x Red Angus heifers (initial mean body weight [BW] of 246 kg) raised on Tifton 85 pasture. The animals were randomly assigned to four treatments: 1) control (no supplementation); 2) addition of 2 g functional oil/animal/day, composed of 70% cashew oil and 30% castor oil; 3) addition of 4 g functional oil/animal/day, composed of 70% cashew oil and 30% castor oil, and 4) addition of 0.2 g monensin sodium/animal/day. The biomass availability and forage on offer were 5,940 kg dry matter/ha and 7.0 kg dry matter/100 kg BW/day, respectively. The average proportion of leaf blade, sheath plus stem and senescent material was 17.6%, 55.0% and 27.4%, respectively. The mean whole-plant contents of crude protein, neutral detergent fiber and in vitro dry matter digestibility were 8.5%, 72.3% and 42.7%, respectively...

A utilização de óleo funcional como aditivos é uma alternativa em potencial como substituto de agentes antimicrobianos não orgânicos. O trabalho teve como objetivo avaliar o efeito da adição de óleo funciomal, composto de óleos de caju e manona, e da monensina sódica em suplemento protéico-energético no desempenho de novilhas mestiças Nelore x Red Angus, com 14 meses de idade e peso corporal (PC) médio inicial de 246 kg, em pastejo de Tifton 85. Os animais foram distribuídos aleatoriamente em quatro tratamentos: 1) controle (sem suplementação); 2) adição de 2 g/animal/dia de óleo funcional, composto por 70% de óleo de caju e 30% de óleo de mamona, 3) adição de 4 g/animal/dia de óleo funciona, composto 70% de óleo de caju e 30% de óleo de mamona e 4) adição de 0,2 g/animal/dia de monensina sódica. A disponibilidade de biomassa forrageira e a oferta de forragem foram de 5.940 kg de matéria seca/ha e 7,0 kg de matéria seca/100 kg PC/dia. A proporção média de lâmina foliar, bainha mais colmo e material senescente foram de 17,6; 55,0 e 27,4%. Na planta inteira os teores médios de proteína bruta, fibra em detergente neutro e digestibilidade in vitro da matéria seca foram de 8,5%, 72,3% e 42,7%, respectivamente. Efeito significativo foi observado no ganho médio diário das novilhas que receberam monensina (0,576 g/dia) em relação as novilhas que não receberam o suplemento protéico-energético (0,290 g/dia). Já o suplemento com óleo funcional, composto de óleos de caju e mamona, proporcionaram ganhos de peso (0,426 g/dia) semelhantes (P>0,05) aos animais que receberam suplemento com monensina (0,576 g/dia)...

Método de amostragem e caracterização química da forragem consumida por bovinos em pasto consorciado de aveia e azevém / Method of sampling and chemical characterization of forage intake by cattle in pasture ryegrass intercropping oats

O presente ensaio foi conduzido com o objetivo de se estudarem diferentes métodos de amostragem de pasto e de se estimar a composição química da dieta consumida por novilhos Holandeses, mantidos em pastagem consorciada de aveia preta (Avena strigosa Schreb) e azevém (Lolium multiflorum Lam). Os métodos avaliados foram o corte da forragem rente ao solo (CFRS), o pastejo simulado (PSI) e a coleta de extrusa ruminal (CERU). Os teores médios de proteína bruta (PB), nutrientes digestíveis totais (NDT), fibra em detergente neutro (FDN) e fibra em detergente ácido (FDA) foram de 9,7; 62,2; 64,5 e 33,1% para o tratamento CFRS; de 9,8; 65,4; 59,6 e 30,0% para o PSI, e de 11,4; 70,8; 51,6 e 25,5% para CERU, respectivamente. Não houve diferença estatística entre os métodos CFRS e PSI, todavia, em relação ao método CERU, ambos subestimaram a concentração proteica e a energética, e superestimaram a quantidade de parede celular presente na dieta. Conclui-se que a coleta da extrusa ruminal pode ser um método adequado para caracterizar a dieta consumida por novilhos em pastagem consorciada de aveia e azevém.

The experiment was conducted to study different methods of pasture sampling, to estimate the chemical composition of the diet of Holstein steer, and grazing pasture of oat (Avena strigosa Schreb)and ryegrass (Lolium multiflorum Lam). The methods evaluated were Clipping Close by Soil (CCS), Hand-Plucking (HPL) and Rumen Evacuation (REV). The averages for crude protein (CP), total digestible nutrients (TDN), neutral detergent fiber (NDF) and acid detergent fiber (ADF) were 9.7, 62.2, 64.5 and 33.1% for the CCS treatment; 9.8, 65.4, 59.6 and 30.0% for HPL, and 11.4, 70.8, 51.6 and 25.5% for REV, respectively. There was no statistical difference between CCS and HPL methods, however, in relation to the REV method, both underestimated protein and energy concentration, and overestimated the amount of cell walls in the diet. The conclusion is that rumen evacuation may be an adequate method to characterize the diet consumed by steers on oats and ryegrass pastures.

Método de amostragem e caracterização química da forragem consumida por bovinos em pasto consorciado de aveia e azevém / Method of sampling and chemical characterization of forage intake by cattle in pasture ryegrass intercropping oats

O presente ensaio foi conduzido com o objetivo de se estudarem diferentes métodos de amostragem de pasto e de se estimar a composição química da dieta consumida por novilhos Holandeses, mantidos em pastagem consorciada de aveia preta (Avena strigosa Schreb) e azevém (Lolium multiflorum Lam). Os métodos avaliados foram o corte da forragem rente ao solo (CFRS), o pastejo simulado (PSI) e a coleta de extrusa ruminal (CERU). Os teores médios de proteína bruta (PB), nutrientes digestíveis totais (NDT), fibra em detergente neutro (FDN) e fibra em detergente ácido (FDA) foram de 9,7; 62,2; 64,5 e 33,1% para o tratamento CFRS; de 9,8; 65,4; 59,6 e 30,0% para o PSI, e de 11,4; 70,8; 51,6 e 25,5% para CERU, respectivamente. Não houve diferença estatística entre os métodos CFRS e PSI, todavia, em relação ao método CERU, ambos subestimaram a concentração proteica e a energética, e superestimaram a quantidade de parede celular presente na dieta. Conclui-se que a coleta da extrusa ruminal pode ser um método adequado para caracterizar a dieta consumida por novilhos em pastagem consorciada de aveia e azevém.(AU)

The experiment was conducted to study different methods of pasture sampling, to estimate the chemical composition of the diet of Holstein steer, and grazing pasture of oat (Avena strigosa Schreb)and ryegrass (Lolium multiflorum Lam). The methods evaluated were Clipping Close by Soil (CCS), Hand-Plucking (HPL) and Rumen Evacuation (REV). The averages for crude protein (CP), total digestible nutrients (TDN), neutral detergent fiber (NDF) and acid detergent fiber (ADF) were 9.7, 62.2, 64.5 and 33.1% for the CCS treatment; 9.8, 65.4, 59.6 and 30.0% for HPL, and 11.4, 70.8, 51.6 and 25.5% for REV, respectively. There was no statistical difference between CCS and HPL methods, however, in relation to the REV method, both underestimated protein and energy concentration, and overestimated the amount of cell walls in the diet. The conclusion is that rumen evacuation may be an adequate method to characterize the diet consumed by steers on oats and ryegrass pastures.(AU)

Gastric injury and protection against alcohol and acid: influence of perturbations in glutathione metabolism.

This study assessed the role that inhibition of glutathione (GSH) synthesis and decreased GSH peroxidase (GPX) activity in the rat played in modulating gastric injury induced by ethanol and acid and its prevention by 16,16-dimethyl PGE2 (dmPGE2) and the mild irritant, 25% ethanol. Although numerous studies have proposed that GSH may be important in maintaining gastric mucosal defense, the exact role of this antioxidant in protecting the stomach from injury remains undefined. The present study addressed this consideration by blocking the synthesis of GSH and altering the major pathway by which it exhibits its antioxidant activity and determining the effect of these perturbations on gastric injury and protection. Four to six rats were used for each experimental group. GSH synthesis was blocked by the potent and specific inhibitor L-buthionine sulfoximine (BSO), 2 or 6 mmole/kg intraperitoneally. The activity of the major form of GPX, which is selenium dependent and utilizes GSH as a substrate to detoxify hydrogen peroxide and other hydroperoxides, was inhibited by placing animals on a selenium-deficient diet for 6 weeks. Gastric damage was induced by 100% ethanol, 50% ethanol in 150 mM HCl, and 0.75 M HCl. Prevention of such injury was accomplished with oral pretreatment using 25% ethanol or dmPGE2 (5 microgram/kg). The damaging effects of 100% ethanol, 50% ethanol/150 mM HCl, or 0.75% M HCl were not adversely affected by BSO pretreatment even though GSH synthesis was inhibited by as much as 80%. Similarly, inhibition of GPX activity by 58% in adult rats and 98% in weanling rats failed to potentiate the damaging effect of 100% ethanol. Furthermore, with both perturbations in GSH metabolism, the protective action of dmPGE2 and 25% ethanol was maintained. Our results indicate that profound alterations in gastric GSH metabolism by themselves do not aggrevate the injurious effects of ethanol or acid, nor do they prevent the protective action of a prostaglandin or mild irritant.

Evidence for a role of volatile amines in the development of neonatal hypergastrinemia.

We investigated the presence of volatile aliphatic amines by fluorescamine and gas chromatographic-head space analysis in human breast milk and amniotic fluid to assess their role in neonatal hypergastrinemia. These volatile nitrogenous amino acid metabolites have been previously demonstrated to stimulate gastrin release in in vivo and in vitro laboratory preparations. In the present study we demonstrated that these gastrin-stimulatory volatile amines were present in significant concentrations in breast milk during the first several weeks after parturition and in amniotic fluid. The individual amines that were identified in both human milk and amniotic fluid samples were methylamine, dimethylamine, ethylamine, trimethylamine, propylamine, isobutylamine, and butylamine. This study provides indirect evidence to support the possibility that the hypergastrinemia measured in the fetus/neonate during the period immediately before and after birth may be attributable, in part, to the ingestion of fluid containing high concentrations of gastrin-stimulating amines.

Gastric damage caused by acidified ethanol: role of molecular HCl.

This study was undertaken to test the hypothesis that an increase in the concentration of molecular HCl in ethanolic solutions is at least partly responsible for the severity of damage seen with acidified ethanol. To accomplish this goal, we studied the synergistic relationship of HCl and ethanol by holding ethanol constant at 50% (vol/vol) and varying the acid concentration. In another experiment, acid concentration was held constant at 150 mM HCl, and the percentage of ethanol was varied. Our hypothesis was also tested by substituting sulfate for chloride to form H2SO4, a nonpermeant molecular acid. Results of our studies clearly showed that substitution of sulfate for chloride greatly reduced gastric damage, supporting the hypothesis that diffusion of molecular HCl is contributing to the damage by acidifying cells. In all cases, acidified ethanol solutions using HCl were more damaging than the individual components alone, and the severity of the damage caused by 50% ethanol was noted to be dependent on the concentration of HCl. We therefore conclude that the severity of acidified ethanol damage is dependent on cellular acidification caused by diffusion of molecular HCl.

Protective action of oral N-acetylcysteine against gastric injury: role of hypertonic sodium.

N-acetylcysteine (NAC), when administered orally as a 20% solution, is a potent protective agent against gastric injury in the rat stomach induced by absolute ethanol. The present study was undertaken to define the means by which this protection is mediated. The notion that NAC acts as a glutathione precursor was excluded when N-acetylserine (NAS) was noted to be equally protective against alcohol injury. The NAS molecule contains a hydroxyl moiety at the site where NAC contains a sulfhydryl. To orally administer 20% NAC at a neutral pH, NaOH is added to the free acid form to keep NAC in solution. We determined by titration that a sodium concentration of 1.2 M results. Thus it became apparent that the protective effect of NAC might be mediated through the sodium employed to titrate NAC. Accordingly, we examined various sodium salts and assessed their relative protective effects against alcohol injury. Both sodium acetate and sodium chloride in 1 M solutions were found to be equally effective in preventing alcohol injury with the same efficiency as 1 M sodium solutions of NAC and NAS, excluding the acetate portion of NAC and NAS as being of primary importance for protection to occur. Further study, using different concentrations of sodium chloride (i.e., 150-1,000 mM) revealed that the 1 M solution was most optimal in preventing alcohol injury. One molar sodium by itself and when administered as part of the NAC solution also prevented gastric injury by concentrated acid and base.(ABSTRACT TRUNCATED AT 250 WORDS)

Adverse effects of vagotomy on ethanol-induced gastric injury in the rat. Absence of a role for glutathione redox cycle.

Truncal vagotomy is known to aggravate the damaging effects of alcohol-induced gastric injury and prevent the occurrence of adaptive cytoprotection against such injury by a mild irritant. This study was undertaken to determine whether aberrations in glutathione (GSH) metabolism were responsible for these vagotomy-induced effects. Fasted rats (6-8/group) were subjected to truncal vagotomy and pyloroplasty or sham vagotomy and pyloroplasty. One week later they were given 2 ml of oral saline or the mild irritant, 25% ethanol (EtOH). Thirty minutes following such treatment, animals were either sacrificed or orally received 2 ml of 100% EtOH and then were sacrificed 5 min later. At sacrifice, in each experimental group, stomachs were removed and either evaluated macroscopically for the degree of injury involving the glandular gastric epithelium or samples of the mucosa were prepared for measurement of total GSH levels or GSH peroxidase (GPX) and GSH reductase (GRT) activity. In nonvagotomized animals, saline treatment prior to 100% EtOH exposure resulted in injury to the glandular epithelium involving approximately 18%. Treatment with 25% EtOH prior to 100% EtOH exposure virtually abolished this injury. In vagotomized animals, 100% EtOH elicited almost three times the amount of injury observed in the nonvagotomized state and the protective effect of 25% EtOH pretreatment was prevented. Effects of the various treatment modalities on GPX and GRT activity were not significantly different from control values. When mucosal GSH results were plotted against the presence or absence of gastric injury among the various groups studied, no significant correlation was apparent.(ABSTRACT TRUNCATED AT 250 WORDS)

Gastric injury induced by ethanol and ischemia-reperfusion in the rat. Differing roles for lipid peroxidation and oxygen radicals.

This study determined the role that oxygen-derived free radicals played in the production of gastric injury in rats challenged orally with concentrated ethanol or subjected to vascular compromise. In the ethanol study, rats were pretreated with a variety of free radical scavengers or enzyme inhibitors prior to exposing the stomach to 100% ethanol. At sacrifice, the degree of macroscopic damage to the glandular gastric mucosa was quantified. In separate studies, the effects of ethanol on gastric mucosal levels of enaldehydes (malondialdehyde and 4-hydroxynonenal) were examined as an index of lipid peroxidation. Superoxide dismutase and catalase pretreatment were without benefit in reducing injury in our ethanol model, excluding potential contributory roles for the superoxide anion or hydrogen peroxide, respectively. Dimethyl sulfoxide and desferoxamine were likewise without protective capabilities, eliminating a role for the hydroxyl radical. Allopurinol, a xanthine oxidase inhibitor, provided no protection under acute conditions, even though partial protection was noted when administered chronically. Further, enaldehyde levels were not increased over control levels in alcohol-exposed mucosa, indicating no enhanced lipid peroxide formation. In contrast, in animals in which ischemia to the stomach was induced followed by reperfusion, marked gastric injury was observed in combination with enhanced enaldehyde levels. Prevention of enaldehyde formation by a 21-aminosteroid concomitantly prevented injury induced by ischemia-reperfusion. These findings support the conclusion that ischemia-reperfusion injury to the stomach is an oxygen-derived free radical process whereas ethanol-induced injury clearly involved some other process. Although allopurinal was partially protective against ethanol damage when administered chronically, observations in other models of injury suggest that this action is independent of its inhibitory effect on xanthine oxidase.

Protective effect of dimethylthiourea against mucosal injury in rat stomach. Implications for hydroxyl radical mechanism.

The present study was undertaken to determine whether dimethylthiourea (DMTU), a hydroxyl radical scavenger, could prevent gastric injury in the rat stomach induced by various noxious agents. Fasted rats (N = 6-8/group) were given a 1-ml oral bolus of saline or DMTU over the dose range 10-500 mg/kg. After 30 min, animals received 1 ml of 100% ethanol orally and were sacrificed 5 min later. At sacrifice, stomachs were harvested and the degree of macroscopic damage was assessed by planimetry. In selected animals, specimens of gastric mucosa were also processed for histology. Saline pretreatment prior to ethanol exposure resulted in 22.5% injury to the glandular epithelium when assessed macroscopically. DMTU pretreatment prevented such injury in a dose-related fashion with only 2% of the mucosa showing injury with a 500 mg/kg dose (P less than 0.01 vs control). Although the superficial injury involving surface mucous cells induced by ethanol was not altered by DMTU, the deep damage to gastric glands was almost completely prevented. Other experiments in which DMTU was given intraperitoneally demonstrated similar protective effects against ethanol injury. Additional studies showed that indomethacin did not prevent the protective effects of oral or intraperitoneal DMTU, excluding a role for endogenous prostaglandins, and that DMTU was equally protective when administered within minutes or as long as 2 hr prior to ethanol exposure. Furthermore, DMTU was also shown to be protective against gastric injury induced by concentrated acid or base. In in vitro studies in which hydroxyl radicals were actually generated, DMTU was noted to scavenge the hydroxyl radical in a dose-related fashion. The ability of DMTU to prevent gastric injury by three different damaging agents suggests that the hydroxyl radical may play a major role in the pathogenesis of such injury and that DMTU mediated its protective action by scavenging this radical species.

Accumulation of aliphatic amines in gastric juice of acute renal failure patients. Possible cause of hypergastrinemia associated with uremia.

In this study we analyzed by gas chromatographic headspace analysis the composition and concentration of gastrin-stimulatory volatile aliphatic amines in the gastric juice of healthy subjects and acute renal failure patients. We demonstrated that although these aliphatic amines are present in the gastric juice of normal subjects in trace amounts, they accumulate in the gastric juice of uremic subjects. This 30-40-fold elevation in gastric juice amine concentration agreed favorably with the 40-50-fold augmentation in serum gastrin levels in acute renal failure, with a significant association (r = 0.87) existing between these two parameters. It was also determined that a 2-hr hemodialysis procedure resulted in a modest nonparallel decline in both gastric amine and serum gastrin levels. These results support the hypothesis that the accumulation of volatile aliphatic amines in the gastric juice of uremic individuals may induce an activation of the antral G cells, resulting in hypergastrinemia.

Cholecystokinin is a potent protective agent against alcohol-induced gastric injury in the rat. Role of endogenous prostaglandins.

Cholecystokinin is a gastrointestinal hormone known to physiologically regulate pancreatic protein secretion and gallbladder contractility. Some evidence suggests that cholecystokinin is also involved in the maintenance of gastrointestinal mucosal integrity. This study was undertaken to ascertain whether cholecystokinin could prevent the gastric mucosal injury induced by acidified ethanol and what role prostaglandins, and type A and type B cholecystokinin receptors might play in this process. Conscious, fasted rats were given subcutaneous saline or cholecystokinin octapeptide (10-100 micrograms/kg) 30 min before a 1-ml oral gastric bolus of acidified ethanol (150 mM HCl/50% ethanol). Five minutes later, rats were sacrificed and the total area of macroscopic injury quantitated (square millimeters). In additional experiments using a similar protocol, 1 ml of either the cyclooxygenase inhibitor, indomethacin (5 mg/kg), a type A cholecystokinin receptor antagonist, L-364,718 (0.01-1 mg/kg), or the type B cholecystokinin receptor antagonist, L-365,260 (12.5-25 mg/kg) was given intraperitoneally 30 min prior to pretreatment with cholecystokinin octapeptide. Cholecystokinin octapeptide dose-dependently prevented mucosal injury from acidified ethanol (corroborated by histology). The protective effect of cholecystokinin octapeptide was completely negated by L-364,718 and partially reversed by indomethacin, while L-365,260 had no discernible effect in this process. In a further study, cholecystokinin was unable to prevent the damaging effects of aspirin and the inhibition of endogenous prostaglandins. This, it appears that cholecystokinin is able to maintain mucosal integrity in the face of a damaging insult by activation of type A cholecystokinin receptors, an effect mediated, at least in part, through the release of endogenous prostaglandins.

Use of fluorescent hydrophobic dyes in establishing the presence of lipids in the gastric mucus gel layer.

The hydrophobic property of crude samples of canine and porcine mucus was demonstrated by its binding and reactivity with two fluorescent dyes, 1-anilinonaphthalene-8-sulfonic acid (ANS) and 1,6-diphenyl-1,3,5-hexatriene (DPH). The contribution of lipids to these hydrophobic binding sites was indicated by our observations that the DPH-induced fluorescence of both porcine and canine gastric mucus was reduced greater than 75% after lipid extraction. Fluorescence microscopy revealed an extracellular band of intense reactivity in association with the mucus gel layer overlying the rat gastric mucosa that was abolished if the frozen sections were pretreated with lipid solvents. When rats pretreated with indomethacin were injected with a cytoprotective dose of 16,16-dimethyl-PGE2, there was an increase in fluorescence of the gastric perfusate treated with ANS, suggesting that hydrophobic factors, perhaps lipids, were being secreted in association with mucus. These extracellular lipids may play an important role in conferring protective barrier properties to the mucus gel layer.