Role of circadian rhythm and endogenous melatonin in pathogenesis of acute gastric bleeding erosions induced by stress.

Stress that appears as a consequence of burns, surgical trauma and life threatening conditions is a serious clinical entity, can result in acute gastric mucosal lesions. Such stress lesions can develop in response to the imbalance between the aggressive factors promoting mucosal damage and the gastric mucosal defense mechanisms including predominantly gastric blood flow (GBF), biosynthesis of gastroprotective prostaglandins (PG) and enhanced mucus/bicarbonate secretion. Melatonin, a major hormone of pineal gland, whose activity is also abundant in the gastrointestinal tract, was shown to inhibit gastric acid secretion, augment GBF and scavenge free radicals, resulting in the attenuation of stress-induced gastric lesions. Melatonin is released during the night but little is known about the effect of circadian rhythm and day/night alterations in melatonin secretion on the formation of stress-induced gastric lesions. Using rats with intact pineal glands and those with removed pineal glands (pinealectomy) exposed to water immersion and restraint stress (WRS) at both, day and night hours, we studied the effect of light and nocturnal melatonin on the formation of these lesions, and accompanying changes in GBF and plasma melatonin levels. It was found that the gastric mucosa exposed to WRS of various time duration's lasting 1.5, 3 and 6 h, time-dependently increased the number of gastric lesions and this effect was accompanied by the time-dependent fall in the GBF and an increase in the plasma and luminal melatonin levels. Pinealectomy augmented WRS-induced lesions at each time intervals of WRS and produced a marked fall in the GBF and plasma and luminal melatonin levels at each time interval of WRS tested. WRS lesions were significantly reduced at night hours and showed circadian variations in plasma levels melatonin with significantly higher plasma melatonin levels at night than in the day and with a greater magnitude of damage induced in the daily hours than at night hours. WRS-induced gastric mucosal lesions were markedly enhanced in pinealectomized rats, both at day and night, and this was accompanied by a significant fall in plasma melatonin levels Stress that appears as a consequence of burns, surgical trauma and life threatening conditions is a serious clinical entity, can result in acute gastric mucosal lesions. Such stress lesions can develop in response to the imbalance between the aggressive factors promoting mucosal damage and the gastric mucosal defense mechanisms including predominantly gastric blood flow (GBF), biosynthesis of gastroprotective prostaglandins (PG) and enhanced mucus/bicarbonate secretion. Melatonin, a major hormone of pineal gland, whose activity is also abundant in the gastrointestinal tract, was shown to inhibit gastric acid secretion, augment GBF and scavenge free radicals, resulting in the attenuation of stress-induced gastric lesions. Melatonin is released during the night but little is known about the effect of circadian rhythm and day/night alterations in melatonin secretion on the formation of stress-induced gastric lesions. Using rats with intact pineal glands and those with removed pineal glands (pinealectomy) exposed to water immersion and restraint stress (WRS) at both, day and night hours, we studied the effect of light and nocturnal melatonin on the formation of these lesions, and accompanying changes in GBF and plasma melatonin levels. It was found that the gastric mucosa exposed to WRS of various time duration's lasting 1.5, 3 and 6 h, time-dependently increased the number of gastric lesions and this effect was accompanied by the time-dependent fall in the GBF and an increase in the plasma and luminal melatonin levels. Pinealectomy augmented WRS-induced lesions at each time intervals of WRS and produced a marked fall in the GBF and plasma and luminal melatonin levels at each time interval of WRS tested. WRS lesions were significantly reduced at night hours and showed circadian variations in plasma levels melatonin with significantly higher plasma melatonin levels at night than in the day and with a greater magnitude of damage induced in the daily hours than at night hours. WRS-induced gastric mucosal lesions were markedly enhanced in pinealectomized rats, both at day and night, and this was accompanied by a significant fall in plasma melatonin levels with a pronounced reduction in mucosal generation of PGE(2) and GBF and by a small increase in plasma melatonin levels during the dark phase. We conclude that 1) stress-induced gastric bleeding erosions exhibit circadian rhythm with an increase in the day and attenuation at night and that these fluctuations in the formation of stress-induced gastric damage may depend upon the melatonin synthesis 2) the progressive increase in plasma melatonin in pinealectomized animals exposed to various time intervals of WRS suggests that extra-pineal melatonin possibly that derived from gastrointestinal tract, play an important role in the gastric mucosal defense against stress-induced gastric damage.

Nitric oxide (NO)-releasing aspirin exhibits a potent esophagoprotection in experimental model of acute reflux esophagitis. Role of nitric oxide and proinflammatory cytokines.

The purpose of this study was to develop an acute animal model of reflux esophagitis, which would be suitable to induce the esophageal damage caused by gastric acid reflux, thus mimicking the esophageal injury of human gastroesophageal reflux disease (GERD). Global research indicates that GERD is rapidly increasing among the world's population. NSAIDs are known to induce gastrointestinal damage and low doses of aspirin (ASA) have been shown to increase the incidences of GERD in humans. Gastric acid and pepsin secretion and enhanced COX-2 expression were implicated in the pathogenesis of reflux esophagitis, but the effect of selective COX-2 inhibitors against lesions induced by the reflux of gastric acid content into esophagus has not been thoroughly studied. Here, we compared the effect of aspirin (ASA) and so called "safe" nitric oxide (NO) derivative of ASA with those of non-selective and selective cyclooxygenase (COX)-1 and COX-2 in rat model of reflux esophagitis. Reflux esophagitis was induced in anesthetized rats by ligating the pylorus and limiting ridge transitional region between the forestomach and the corpus of stomach. Subsequently, the total gastric reservoir to store gastric juice was greatly diminished, resulting in the reflux of this juice into the esophagus. Rats with esophagitis received intragastric (i.g.) pretreatment either with: 1) vehicle (saline), 2) ASA or NO-ASA (100 mg/kg); 3) the non-selective COX inhibitor, indomethacin (5 mg/kg); 4) the selective COX-1 inhibitor, SC-560 (10 mg/kg), and 5) the selective COX-2 inhibitor, celecoxib (5 mg/kg). In a separate series of rats with reflux oesophagitis, the efficacy of ASA combined with a donor of NO, glyceryl trinitrate (GTN; 10 mg/kg i.g.) to prevent esophageal mucosal injury was investigated. Four hours after induction of esophagitis the gross mucosal damage was graded with a macroscopic lesion index (LI) from 0-6. The esophageal blood flow (EBF) was determined by H2-gas clearance technique, the oesophageal mucosal and blood samples were collected for histology and analysis of the RT-PCR expression and release of proinflammatory cytokines IL-1ß, TNF-α and IL-6 using specific ELISA. The exposure of the esophagus to reflux of gastric acid time-dependently increased the esophageal LI and morphologic damage, and decreased EBF with the most significant changes observed at 4 hrs after the ligation procedure. The pretreatment with native ASA in the dose that suppressed the generation of mucosal PGE2, enhanced gross and histologic esophageal damage and produced a significant fall in EBF. NO-ASA or ASA coupled with GTN counteracted the aggravation of the damage and accompanying fall in EBF when compared with native ASA applied alone to rats with esophagitis. The proinflammatory cytokines IL-1ß and TNF-α were overexpressed in rats with esophagitis and those pretreated with ASA but this effect was significantly attenuated by NO-ASA. Plasma IL-1ß, TNF-α and IL-6 were negligible in the intact rats but significantly increased in those with esophagitis, with this effect being further enhanced by non-selective (indomethacin) and selective (SC-560, celecoxib) COX-1 and COX-2 inhibitors. We conclude that conventional NSAID such as aspirin augments esophagitis, while NO-ASA exerts the beneficial protective effect against reflux esophagitis via the enhancement of esophageal microcirculation due to NO release and an inhibitory effect on expression and release of pro-inflammatory cytokines.

Skeletal muscle relaxants inhibit rat tracheal smooth muscle tone in vitro.

Neuromuscular blocking drugs (NMBD) can inhibit not only nicotinic but also muscarinic (M) receptors and thereby affect not only skeletal but also smooth muscle (SM) tone. A selective postjunctional muscarinic inhibition would relax, while prejunctional inhibition of muscarinic M2 receptor might hasten SM contraction thereby increasing the risk of bronchospasm. In rat tracheal rings in vitro we evaluated the effects of cumulative concentrations of some NMBD and M receptor blocking agents for their effects on tracheal smooth muscle (TSM) tone pre-contracted with carbachol (CARB; 5 x 10(-7)M or 10(-6)M), pilocarpine (PILO; 5 x 10(-6)M), or by electrical field stimulation. The NMBDs produced relaxation in the preparations precontracted with CARB or PILO. The order of potency after CARB (10(-6)M) was (EC(50)): 4-DAMP (9.8) >atropine (9.2) >methoctramine (6.4) >pancuronium (6.0) >mivacurium (5.8) >cisatracurium (5.6) >gallamine (5.2) >rocuronium (4.8) >succinylcholine (2.9); NMBDs also partially prevented contraction elicited by the electrical field stimulation. We demonstrated that the clinically used NMBD that were examined produced rat TSM relaxation, probably by predominantly blocking postjunctional muscarinic receptors.

Changes in insulin like growth factors, myostatin and vascular endothelial growth factor in rat musculus latissimus dorsi by poly-3-hydroxybutyrate implants.

The present study aimed at researching the synergistic effect between an ectopic bone substitute and surrounding muscle tissue. To describe this effect, changes of insulin like growth factors (IGF1, IGF2), myostatin (GDF8) and vascular endothelial growth factor (VEGF) mRNA content of 12 Wistar-King rats musculus latissimus dorsi with implanted poly-3-hydroxybutyrate (PHB) scaffold were examined after 6 and 12 weeks. At each time interval six rats were killed and implants and surrounding tissues prepared for genetic evaluation. Eight rats without any implants served as controls. RNA was extracted from homogenized muscle tissue and reverse transcribed. Changes in mRNA content were measured by Real-Time PCR using specific primers for IGF1, IGF2, GDF8 and VEGF. Comparing the level of VEGF mRNA in muscle after 6 and 12 weeks to the controls, we could assess a significant increase of VEGF gene expression (p<0.05) whereas the level of mRNA expression was higher after 6 than after 12 weeks of treatment. Expression of IGF1 gene was also significantly increased as compared to the controls over the observed period of time (p<0.05). In the case of the IGF2 gene, the expression was significantly elevated after 6 weeks (p<0.05), but not significantly increased after 12 weeks (p>0.05). We observed a significantly decreased GDF8 gene expression (p<0.05) both after retrieval of implants after 6 as well as after 12 weeks. Moreover, mRNA level of GDF8 after 6 and 12 weeks were comparable the same. Our results show that PHB implants in rat musculus latissimus dorsi interact with the surrounding muscle tissue. This interaction works itself on growth potential of the muscle.

Application of a diagnostic-therapeutic procedure using implant-supported dental prosthesis as a preventive therapy for candidiasis of upper gastrointestinal tract in complete denture users.

Our previous studies demonstrated that the use of acrylic based prosthesis in edentulous patients had a direct impact on the increased incidence of oral mycosis and further episodes of mycosis in the digestive tract. This dependency is associated with formation of a space between the surface of the prostheses and adhering mucosal membrane, where a specific micro environment is being formed, which - as stated - creates a superior breeding ground mainly for microorganisms of the genus Candida.