1-Methylnicotinamide (MNA) is one of the major derivatives of nicotinamide, which was recently shown to exhibit antithrombotic and antiinflammatory actions. However, it is not yet known whether MNA ...affects gastric mucosal defense. The effects of exogenous MNA were studied on gastric secretion and gastric lesions induced in rats by 3.5 h of water immersion and water restraint stress (WRS) or in rats administered 75% ethanol. MNA 6.25-100 mg/kg intragastrically (i.g.) led to a dose-dependent rise in the plasma MNA level, inhibited gastric acid secretion, and attenuated these gastric lesions induced by WRS or ethanol. The gastroprotective effect of MNA was accompanied by an increase in the gastric mucosal blood flow and plasma calcitonin gene-related peptide (CGRP) levels, the preservation of prostacyclin (PGI(2)) generation (measured as 6-keto-PGF1alpha), and an overexpression of mRNAs for cyclooxygenase (COX)-2 and CGRP in the gastric mucosa. R-3-(4-Fluoro-phenyl)-2-5-(4-fluoro-phenyl)-benzofuran-2-ylmethoxycarbonylamino-propionic acid (RO 324479), which is the selective antagonist of IP/PGI(2) receptors, reversed the effects of MNA on gastric lesions and GBF. MNA-induced gastroprotection was attenuated by suppression of COX-1 5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole; SC-560 and COX-2 4-(4-methylsulfonylphenyl)-3-phenyl-5H-furan-2-one; rofecoxib activity, capsaicin denervation, and by the pretreatment with CGRP(8-37) or capsazepine. Addition of exogenous PGI(2) or CGRP restored the MNA-induced gastroprotection in rats treated with COX-1 and COX-2 inhibitors or in those with capsaicin denervation. WRS enhanced MDA content while decreasing superoxide dismutase (SOD) activity in the gastric mucosa, but pretreatment with MNA reversed these changes. MNA exerts potent gastroprotection against WRS damage via mechanisms involving cooperative action of PGI(2) and CGRP in preservation of microvascular flow, antioxidizing enzyme SOD activity, and reduction in lipid peroxidation.
Orexigenic peptides are group of endocrine hormones exerting a pleiotropic influence on many physiological functions including regulation of the feeding behaviour and energy expenditure, release of ...growth hormone (GH) and inotropic effects on the heart. Some of these peptides such as ghrelin, originally identified in the gastric mucosa, has been involved not only in control of food intake and growth hormone release but also exerts the immunomodulatory and anti-inflammatory properties. This review summarizes the recent attempts to prove the concept that orexigenic peptides such as ghrelin, orexin-A and obestatin besides playing an important role in the mechanism of food intake, exhibit a potent gastroprotective action against the formation of acute gastric mucosal injury induced by various ulcerogens. This protective effect depends upon vagal activity and hyperemia mediated by NOS/NO and COX/PG systems and CGRP released from sensory afferent nerves. In addition, the appetite peptides such as ghrelin and orexin-A are implicated in the mechanism of the healing of preexisting gastric ulcers due to an activation of specific GHS-R1a and OX-R1 receptors and PG/COX system.
Limitation of the stomach damage by its earlier brief ischemia and reperfusion before prolonged ischemia is defined as gastric ischemic preconditioning but whether such brief ischemia of remote ...organs like heart or liver can also attenuate the gastric damage caused by longer and severe ischemia–reperfusion remains unknown. The cardiac, hepatic and gastric preconditioning were induced by brief ischemia (occlusion of coronary, hepatic and celiac arteries twice for 5 min) applied 30 min before 3 h of ischemia/reperfusion. Standard 3 h ischemia–reperfusion of the stomach produced numerous gastric lesions, decreased gastric blood flow and mucosal prostaglandin E
2 generation and increased expression and plasma release of interleukin-1β and tumor necrosis factor-alpha (TNF-α). These effects were significantly attenuated by brief cardiac, hepatic and gastric preconditioning which upregulated cyclooxygenase-2 mRNA but not cyclooxygenase-1 mRNA. The protective effects of brief gastric, cardiac and hepatic preconditioning were attenuated by selective cyclooxygenase-1 and cyclooxygenase-2 inhibitors and capsaicin denervation. We conclude that brief ischemia of remote preconditioning such as heart or liver protects gastric mucosa against severe ischemia–reperfusion-induced gastric lesions as effectively as local preconditioning of the stomach itself via the mechanism involving prostaglandin derived from cyclooxygenase-1 and cyclooxygenase-2 and the activation of sensory nerves releasing calcitonin gene-related peptide (CGRP) combined with the suppression of interleukin-1β and TNF-α expression and release.
Melatonin, a major hormone of pineal gland, was recently shown to attenuate acute gastric lesions induced by strong irritants because of the scavenging of free radicals but its role in ulcer healing ...has been little investigated. In this study we compared the effects of intragastric (i.g.) administration of melatonin and its precursor, L‐tryptophan, with or without concurrent treatment with luzindole, a selective antagonist of melatonin MT2 receptors, on healing of chronic gastric ulcers induced by serosal application of acetic acid (ulcer area 28 mm2). The involvement of endogenous prostaglandins (PG), nitric oxide (NO) and sensory nerves in ulcer healing action of melatonin and L‐tryptophan was studied in rats treated with indomethacin and NG‐nitro‐L‐arginine (L‐NNA) to suppress, respectively, cyclo‐oxygenases (COX) and NO synthases or in those with functionally deactivated sensory nerves with capsaicin. The influence of melatonin on gastric secretion during ulcer healing was tested in separate group of rats with gastric ulcer equipped with gastric fistulas (GF). At day 8 and 15 upon the ulcer induction, the area of gastric ulcers was measured by planimetry, the mucosal blood flow (GBF) was determined by H2‐gas clearance technique and gastric luminal NO2–/NO3– levels was assessed by Griess reaction. Plasma melatonin and gastrin levels were measured by specific radioimmunoassay (RIA). Biopsy mucosal samples were taken for expression of constitutive NO‐synthase (cNOS) and inducible NOS (iNOS) by reverse transcriptase‐polymerase chain reaction (RT‐PCR). Melatonin (2.5–20 mg/kg‐d i.g.) and L‐tryptophan (25–100 mg/kg‐d i.g.) dose‐dependently accelerated ulcer healing, the dose inhibiting by 50% (ED50) of ulcer area being 10 and 115 mg/kg, respectively. This inhibitory effect of melatonin (10 mg/kg‐d i.g.) and L‐tryptophan (100 mg/kg‐d i.g.) on ulcer healing was accompanied by a significant rise in the GBF at ulcer margin and an increase of plasma melatonin, luminal NO2–/NO3– and plasma gastrin levels. Gastric acid and pepsin outputs were significantly inhibited during the ulcer healing in melatonin‐treated gastric mucosa as compared with those in vehicle‐treated animals. Luzindole abolished completely the healing effects of melatonin and L‐tryptophan and attenuated significantly the rise in plasma gastrin evoked by the hormone and its precursor. Indomethacin (5 mg/kg‐d i.p), that blocked PG biosynthesis by 90% or L‐NAME (20 mg/kg i.v), inhibitor of NOS, that suppressed luminal NO release, attenuated significantly melatonin and L‐tryptophan‐induced acceleration of ulcer healing and accompanying rise in GBF at ulcer margin and luminal NO release. The melatonin‐induced acceleration of ulcer healing, hyperemia at ulcer margin and increase in the release of NO were enhanced when L‐arginine but not D‐arginine was added to L‐NAME. The ulcer healing and the GBF effects of melatonin and L‐tryptophan were significantly impaired in rats with capsaicin‐induced denervation of sensory nerves and both, ulcer healing and the hyperemia at ulcer margin were restored in these rats by addition of exogenous CGRP to melatonin and L‐tryptophan. Expression of cNOS mRNA was detected by RT‐PCR in the intact gastric mucosa as well as at the edge of gastric ulcers treated with both, vehicle and melatonin, while iNOS mRNA that was undetectable in the intact gastric mucosa, appeared during ulcer healing and especially this was strongly up‐regulated in the melatonin‐treated gastric mucosa. We conclude that (1) exogenous melatonin and that derived from its precursor, L‐tryptophan, accelerate ulcer healing probably via interaction with MT2 receptors; (2) this ulcer healing action is caused by an enhancement by melatonin of the microcirculation at the ulcer margin possibly mediated by COX‐derived PG and NO because of overexpression of iNOS and (3) gastrin, which exhibits trophic activity in the gastric mucosa and calcitonin gene related peptide (CGRP), released from sensory nerves, may also contribute to the ulcer healing action of melatonin.
Various organs, including heart, kidneys, liver or brain, respond to brief exposures to ischemia with an increased resistance to severe ischemia/reperfusion and this phenomenon is called ...“preconditioning”. No study so far has been undertaken to check whether such short, repeated gastric ischemic episodes protect gastric mucosa against severe damage caused by subsequent prolonged ischemia/reperfusion and, if so, what could be the mechanism of this phenomenon. The ischemic preconditioning was induced by short episodes of gastric ischemia (occlusion of celiac artery from one to five times, for 5 min each) applied 30 min before prolonged (30 min) ischemia followed by 3 h of reperfusion or 30 min before topical application of strong mucosal irritants, such as 100% ethanol, 25% NaCl or 80 mM taurocholate. Exposure to regular 30-min ischemia, followed by 3-h reperfusion, produced numerous severe gastric lesions and significant fall in the gastric blood flow and prostaglandin E
2 generation. Short (5-min) ischemic episodes (1–5 times) by itself failed to cause any gastric lesions, but significantly attenuated those produced by ischemia/reperfusion. This protection was accompanied by a reversal of the fall in the gastric blood flow and prostaglandin E
2 generation and resembled that induced by classic gastric mild irritants. These protective and hyperemic effects of standard preconditioning were significantly attenuated by pretreatment with cyclooxygenase-2 and cyclooxygenase-1 inhibitors, such as indomethacin, Vioxx, resveratrol and nitric oxide (NO)-synthase inhibitor,
N
G-nitro-
l-arginine (
l-NNA). The protective and hyperemic effects of standard preconditioning were restored by addition of 16,16 dm prostaglandin E
2 or
l-arginine, a substrate for NO synthase, respectively. Gastroprotective and hyperemic actions of standard ischemic preconditioning were abolished by pretreatment with capsaicin-inactivating sensory nerves, but restored by the administration of exogenous CGRP to capsaicin-treated animals. Gene and protein expression of cyclooxygenase-1, but not cyclooxygenase-2, were detected in intact gastric mucosa and in that exposed to ischemia/reperfusion with or without ischemic preconditioning, whereas cyclooxygenase-2 was overexpressed only in preconditioned mucosa. We conclude that: (1) gastric ischemic preconditioning represents one of the most powerful protective interventions against the mucosal damage induced by severe ischemia/reperfusion as well as by topical mucosal irritants in the stomach; (2) gastric ischemic preconditioning resembles the protective effect of “mild irritants” against the damage by necrotizing substances in the stomach acting via “adaptive cytoprotection” and involves several mediators, such as prostaglandin derived from cyclooxygenase-1 and cyclooxygenase-2, NO originating from NO synthase and sensory nerves that appear to play a key mechanism of gastric ischemic preconditioning.
Bereits im vergangenen Jahrhundert begannen die neueren rechtsphilosophischen und strafrechtsdogmatischen Auseinandersetzungen um den rechtfertigenden Notstand. Seitdem ist der ...Strafrechtswissenschaft bewußt, daß dieses Rechtsinstitut stark irreguläre Züge aufweist. Worin diese Irregularität liegt, macht ein vergleichender Blick auf die Notwehrregelung deutlich.
Wer sich in einer Notlage befindet, darf zwangsweise auf Rechtsgüter eines Dritten zugreifen. Notwehr- und Notstandsrecht gestatten das. Die Eingriffsbefugnis erweist beide Regelungen als Ausnahmen vom Grundsatz des staatlichen Gewaltmonopols.
Das staatliche Gewaltmonopol ist von zentraler Bedeutung für den modernen, den Schrecken der Anarchie und des Bürgerkriegs abgerungenen Staat. Es behält die gerechtfertigte Ausübung von Zwang prinzipiell den zuständigen staatlichen Organen vor; auf seiten der Bürger entspricht ihm eine generelle Friedenspflicht. Die Notrechte schränken den staatlichen Rechtsschutzvorrang gerade in den besonders heiklen Fällen akut zugespitzter Konflikte ein.
Angiotensin-(1-7) Ang-(1-7) is a major vasoactive metabolite of angiotensin I (Ang I), both being important components of the renin-angiotensin system (RAS). Ang-(1-7) acting via Mas receptor was ...documented in kidneys, heart, brain, and gastrointestinal (GI)-tract. We studied the gastroprotective activity of exogenous Ang-(1-7) in rats exposed to water immersion and restraint stress (WRS) without or with A-779 d-Ala7-Ang-(1-7), an antagonist of Ang-(1-7) Mas receptors, AVE 0991 (5-formyl-4-methoxy-2-phenyl-14-2-(ethylaminocarbonylsulfonamido)-5-isobutyl-3-thienyl-phenyl-methyl-imidazole), the agonist of Ang-(1-7) receptor, as well as the inhibition of nitric-oxide (NO) synthase, the suppression of cyclo-oxygenase (COX)-1 (indomethacin, SC-560 5-(4-chloro-phenyl)-1-(4-methoxyphenyl)-3-trifluoromethyl-pyrazole), the activity COX-2 (rofecoxib), and denervation with capsaicin. The mRNA expression of constitutively expressed nitric-oxide synthase (cNOS), inducible nitric-oxide synthase (iNOS), interleukin (IL)-1β, and tumor necrosis factor (TNF)-α was analyzed by reverse transcription polymerase chain reaction. The WRS lesions were dose-dependently reduced by pretreatment with Ang-(1-7), which also caused an increase in gastric blood flow (GBF) and luminal content of NO. COX-1 and COX-2 inhibitors or L-NNA (N5-imino(nitroamino)methyl-L-ornithine) reversed the reduction in lesion number and the rise in GBF evoked by Ang-(1-7). Ang II augmented the WRS lesions, decreased GBF and increased the plasma IL-1β and TNF-α levels. Capsaicin denervation attenuated the reduction of Ang-(1-7)-induced gastric lesions and the rise in GBF; these effects were restored by supplementation with calcitonin gene-related peptide (CGRP). The cNOS mRNA was upregulated while iNOS, IL-1β and TNF-α mRNAs were downregulated in Ang-(1-7)-pretreated rats. We conclude that Ang-(1-7), in contrast to Ang II, which worsened WRS ulcerogenesis, affords potent gastroprotection against WRS ulcerogenesis via an increase in GBF mediated by NO, endogenous prostaglandins, sensory neuropeptides, and anti-inflammatory action involving the inhibition of proinflammatory markers iNOS, IL-1β, and TNF-α.
A photonic ultra-wideband (UWB) pulse generator based on relaxation oscillations of a semiconductor laser is proposed and experimentally demonstrated. We numerically simulate the modulation response ...of a direct modulation laser (DML) and show that due to the relaxation oscillations of the laser, the generated signals with complex shape in time domain match the Federal Communications Commission (FCC) mask in the frequency domain. Experimental results using a DML agree well with simulation predictions. Furthermore, we also experimentally demonstrate the generation of FCC compliant UWB signals by externally injecting a distributed feedback (DFB) laser.
Reflux esophagitis is a common clinical entity in western countries with approximately 30% of the population experiencing the symptoms at least once every month. The imbalance between the protective ...and aggressive factors leads to inflammation and damage of the esophageal mucosa. We compared the effect of exogenous melatonin and melatonin derived endogenously from L‐tryptophan with that of pantoprazole or ranitidine in acid reflux esophagitis due to ligation of the rat pylorus and the limiting ridge between the forestomach and the corpus. Four hours after the induction of gastric reflux, an increase in mucosal lesions associated with edema of the submucosa and with the infiltration of numerous neutrophils and the fall in esophageal blood flow (EBF) were observed. Both melatonin and L‐tryptophan or pantoprazole significantly reduced the lesion index (LI) and raised the EBF. Pinealectomy that significantly decreased plasma melatonin levels aggravated LI and these effects were reduced by melatonin and L‐tryptophan. Luzindole, the MT2 receptor antagonist, abolished the melatonin‐induced reduction in LI and the rise in EBF. L‐NNA and capsaicin that augmented LI and decreased EBF, also significantly reduced melatonin‐induced protection and hyperemia; both were restored with L‐arginine and calcitonin gene–related peptide (CGRP) added to melatonin. Upregulation of IL‐1β and TNF‐α mRNAs and plasma IL‐1β and TNF‐α levels were significantly attenuated by melatonin and L‐tryptophan. We conclude that melatonin protects against acid reflux‐induced damage via activation of MT2 receptors mediated by NO and CGRP released from sensory nerves and the suppression of expression and release of TNF‐α and IL‐1β.
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