Involvement of α2-Adrenoceptors in the Gastric Protective Effect of Nitroglycerin Against Acidified Ethanol-Induced Mucosal Injury

Clinical observations reveal that alcohol intake is associated with an increase in upper gastrointestinal hemorrhage requiring hospitalization and that nitroglycerin or long-acting nitrates lower this risk. Nitroglycerin, a gastric vasodilator that can increase gastric fluid volume, protects the rodent stomach against damage, including that caused by 70% ethanol. Blockade of α₂-adrenoceoptors attenuates gastric protection by intragastric nicotine against 40% ethanol. We tested the hypothesis that the protective effect of nitroglycerin is mediated by an increase in gastric fluid volume and α₂-adrenoceoptors. Nitroglycerin, 5 mg/kg, vehicle, or acidified ethanol was administered intragastrically. In study 1 acidified ethanol-induced mucosal injury was measured. In study 2 the effect of increasing gastric volume (1 ml/kg) on mucosal injury was assessed. In study 3 the effect of yohimbine (α₂-adrenoceoptor antagonist), 5 mg/kg subcutaneously, on the nitroglycerein-mediated protective effect was determined. Results showed that nitroglycerin significantly attenuated the number and length of mucosal lesions induced by acidified ethanol. Increase in gastric fluid volume by exogenously administered saline did not alter the protective effect. Yohimbine blocked the nitroglycerin-mediated protection. These experimental data are consistent with the observation that nitrates lower the risk of ethanol-induced gastrointestinal complications. α₂-Adrenoceoptors are responsible in part for the protective effect of nitroglycerin.     

Effects of Polaprezinc on Lipid Peroxidation, Neutrophil Accumulation, and TNF-α Expression in Rats with Aspirin-Induced Gastric Mucosal Injury

We examined the roles of lipid peroxidation, neutrophil accumulation, and inflammatory cytokines in the protective effect of polaprezinc against aspirin-induced gastric mucosal injury in rats. The intragastric administration of acidified aspirin induced hyperemia and hemorrhagic erosions in rat stomachs. The increase in the total gastric erosive area after aspirin administration was significantly inhibited in a dose-dependent manner by treatment with polaprezinc. The increases in thiobarbituric acid-reactive substances and tissue-associated myeloperoxidase activity 3 hr after aspirin administration were significantly inhibited by pretreatment with polaprezinc. The gastric concentration of TNF- increased after aspirin administration, and the increase was also inhibited in a dose-dependent manner by treatment with polaprezinc. The peak expression of TNF- mRNA 1 hr after aspirin administration was inhibited by 30 mg/kg of polaprezinc. Based on these data, the beneficial effects of polaprezinc on aspirin-induced gastric mucosal injury may be attributed to its antioxidative and antiinflammatory properties.     

Does Helicobacter pylori Exacerbate Gastric Mucosal Injury in Users of Nonsteroidal Anti-Inflammatory Drugs? A Multicenter,Retrospective, Case-Control Study

Background/Aims

The interaction between nonsteroidal anti-inflammatory drugs (NSAIDs) and Helicobacter pylori remains controversial. We retrospectively investigated whether H. pylori infection exacerbates severe gastric mucosal injury among chronic NSAID users.

Methods

From January 2010 to December 2013, a total of 245 long-term NSAID (including low-dose aspirin) users who had undergone an esophagogastroduodenoscopy and had been evaluated for H. pylori infection were enrolled at Okayama University Hospital and Tsuyama Chuo Hospital. The degree of gastric mucosal injury was assessed according to the modified Lanza score (MLS). Severe gastric mucosal injury was defined as an MLS ≥4. Univariate and multivariate logistic regression analyses were performed.

Results

In the univariate analysis, age ≥75 years (odds ratio [OR], 2.4; 95% confidence interval [CI], 1.3 to 4.2), H. pylori-positivity (OR, 2.0; 95% CI, 1.2 to 3.5), and the concomitant use of proton pump inhibitors (PPIs) (OR, 0.48; 95% CI, 0.26 to 0.86) were significantly associated with severe gastric mucosal injury. The multivariate analysis was adjusted by age and sex and demonstrated that H. pylori-positivity (OR, 1.8; 95% CI, 1.0 to 3.3) and the concomitant use of PPIs (OR, 0.53; 95% CI, 0.28 to 0.99) significantly contributed to severe gastric mucosal injury.

Conclusions

H. pylori infection exacerbates severe gastric mucosal injury among chronic NSAID users.     

Value of Digoxin in Heart Failure and Sinus Rhythm: New Features of an Old Drug?

Digoxin has been a controversial drug since its introduction >200 years ago. Although its efficacy in patients with heart failure and atrial fibrillation is clear, its value in patients with heart failure and sinus rhythm has often been questioned. In the 1980s, reports of some large-scale trials indicated that digoxin, with or without vasodilators or angiotensin-converting enzyme inhibitors, reduced signs and symptoms of congestive heart failure and improved exercise tolerance. This beneficial influence was mainly found in patients with more advanced heart failure and dilated ventricles, whereas the effect in those with mild disease appeared to be less pronounced. In the last few years, new data have shown that digoxin may also have clinical value in mild heart failure, either when used in combination with other drugs or when administered alone. As neurohumoral activation has increasingly been recognized to be a contributing factor in the disease progression of chronic heart failure, the modulating effects of digoxin on neurohumoral and autonomic status have received more attention. Also, there is evidence that relatively low doses of digoxin may be at least as effective as higher doses and have a lower incidence of side effects. Further, the recognition that the use of digoxin too early after myocardial infarction may be harmful and the development of other drugs, in particular angiotensin-converting enzyme inhibitors, have obviously changed the place of digoxin in the treatment of chronic heart failure. The large-scale survival trial by the Digitalis Investigators Group (DIG), whose preliminary results have recently been presented, has shown that although digoxin has a neutral effect on total mortality during long-term treatment, it reduces the number of hospital admissions and deaths due to worsening heart failure. The potentially new features of the old drug digoxin are discussed in this review.     

Oxygen Radical Induced Gastric Mucosal Cell Death: Apoptosis or Necrosis?

Reactive oxygen species (ROS) and resultant oxidative damage is a common pathway for gastric mucosal injury. This study was undertaken to determine whether apoptosis or necrosis was responsible for hydrogen peroxide (a representative ROS)-induced gastric mucosal death and whether caspase cascade blockade could prevent this process. AGS cells (human gastric adenocarcinoma cells) were exposed to hydrogen peroxide (H(2)O(2)), 0.5-2 mM, from 6 to 24 h. Lactic dehydrogenase (LDH) measured necrosis, whereas Caspase-3 and PARP activation and DNA-histone complex formation measured apoptosis. In addition, AGS cells received no pretreatment or preincubation for 1 h with 50-100 muM z-VAD, a pan-caspase inhibitor, and were then treated with 1-2 mM H(2)O(2). With high concentrations of H(2)O(2), cell death was predominantly necrotic, whereas lower concentrations evoked time and concentration dependent apoptosis. Furthermore, z-VAD pretreatment prevented oxidant induced apoptosis and necrosis. Since caspase cascade blockade prevents both processes, our results support the hypothesis that H(2)O(2) induced cell death is predominantly a caspase-mediated apoptosis.     

Effect of Stimulation of Mucosal HCO‐ Secretion on Acid-Induced Injury to Porcine Duodenal Mucosa

The effect of stimulation of duodenal mucosal bicarbonate secretion with vasoactive intestinal peptide (VIP) on acid-induced damage to the duodenal mucosa was studied in anaesthetized pigs in which bile and pancreatic juice were diverted from the duodenum. Mucosal damage was quantitatively assessed histologically, and mucosal blood flow was determined by means of radioactively labelled microspheres. Compared with placebo, intravenous infusion of VIP (500 pmol/kg/h) significantly stimulated duodenal mucosal bicarbonate secretion (47 ± 13 versus 249 ± 53 μmol/h) without concomitant changes in mucosal blood flow (51.5 ± 7.8 versus 48.5 ± 9.1 ml/min/100g) or arterial bicarbonate concentration (24.2 ± 1.1 versus 23.4 ± 0.9 mM). The same dose of VIP increased the acid disappearance rate in the duodenum (2.2 ±0.14 versus 3.3 ± 0.09 mmol/h) and reduced the extent of damage to the duodenal surface (16 ± 2% versus 7 ± 2%) during duodenal infusion of 0.03 M HC1 but not 0.1 M HCI. We conclude that the protection offered by VIP against the small dose of acid is most likely secondary to the effect of VIP on mucosal bicarbonate secretion. Thus, this study suggests that duodenal mucosal bicarbonate secretion, independent of mucosal blood flow, is an integral factor in duodenal mucosal defence.     

REVIEW: Ischemia—Reperfusion Injury of the Intestine and Protective Strategies Against Injury

Ischemia-reperfusion injury of the intestine is a significant problem in abdominal aortic aneurysm surgery, small bowel transplantation, cardiopulmonary bypass, strangulated hernias, and neonatal necrotizing enterocolitis. It can also occur as a consequence of collapse of systemic circulation, as in hypovolemic and septic shock. It is associated with a high morbidity and mortality. This article is a comprehensive review of the current status of the molecular biology and the strategies to prevent ischemia-reperfusion injury of the intestine. Various treatment modalities have successfully been applied to attenuate reperfusion injury in animal models of reperfusion injury of the intestine. Ischemic preconditioning has been found to be the most promising strategy against reperfusion injury during the last few years, appearing to increase the tolerance of the intestine to reperfusion injury. Although ischemic preconditioning has been shown to be beneficial in the human heart and the liver, prospective controlled studies in humans involving ischemic preconditioning of the intestine are lacking. Research focused on the application of novel drugs that can mimic the effects of ischemic preconditioning to manipulate the cellular events during reperfusion injury of the intestine is required.     

Mucosal defense. New avenues for treatment of ulcer disease?

Ulceration likely occurs as a consequence of a progressive failure of the various components of mucosal defense. Present therapy for peptic ulcer is focused almost entirely on reduction of luminal "aggressive" factors. Future advances in the treatment of ulcer disease is likely dependent on our developing a better understanding of mucosal defense.     

Apoptosis: A New Mechanism of Lethal Myocardial “Reperfusion Injury”?

Journal of Thrombosis and Thrombolysis -