Gastric Ischemia-reperfusion Injury Research Articles

Effect of oxytocin on gastric ischemia-reperfusion injury in rats

The effect of peripherally administered oxytocin (OT) on gastric ischemia-reperfusion injury (GI-RI) and its possible mechanism were investigated. The Sprague-Dawley (SD) rats were randomly divided into different treatment groups (n = 6). The animal GI-RI model was established by clamping the celiac artery for 30 min to induce ischemia and then released to allow reperfusion for 1 h, and the degree of GI-RI was assessed by scoring the gastric mucosal damage index (GMDI), the gastric fluid output, gastric fluid output, gastric acidity were measured and the surgical preparations of vagotomy and sympathectomy were used to investigate the possible mechanism of OT on GI-RI. The results were as follows. Compared with the control group (NS plus GI-R only, GMDI 121.33 ± 10.40, n = 6), the intraperitoneal (ip) administration of oxytocin (20, 100 μg/0.5 mL) obviously attenuated GI-RI (P < 0.05), GMDI were 82.33 ± 14.26, 53.5 ± 5.58 respectively (n = 6); the gastric fluid output and the gastric acidity (evaluated by pH) of the control group were (430.17 ± 87.36) μL, 1.55 ± 0.25 (n = 6), and those of the OT group were (102.45 ± 48.00) μL, 2.65 ± 0.40 (n = 6) respectively; differences had statistical significance (P < 0.01). The effect of oxytocin was reversed by atosiban, a selective oxytocin receptor antagonist. The GMDI of the group given atosiban 10 min before OT was 138.17 ± 24.06 (n = 6), which had no significant difference with the control group. Oxytocin further attenuated GI-RI after vagotomy and sympathectomy (GMDI 6.83 ± 8.89, 29.67 ± 5.54, n = 6), compared with the GI-R group and the oxytocin group (P < 0.01). These results indicated that the oxytocin could significantly protect gastric mucosal against injury induced by ischemia-reperfusion, and the oxytocin receptor was involved. This effect of oxytocin may be mediated through the vagus and sympathetic nerve, and then lead to the reduction of gastric juice output and the depression of gastric acidity.

Nuclear factor-κB inhibition by pyrrolidinedithiocarbamate attenuates gastric ischemia-reperfusion injury in rats

Pyrrolidinedithiocarbamate (PDTC) is a potent antioxidant and an inhibitor of nuclear factor-kappaB (NF-kappaB). The present study examined the impact of PDTC preconditioning on gastric protection in response to ischemia-reperfusion (I/R) injury to the rat stomach. Male Wistar rats were recruited and divided into 3 groups (n = 7). One group was subjected to gastric ischemia for 30 min and reperfusion for 1 hour. The second group of rats was preconditioned with PDTC (200 mg/kg body mass i.v.) 15 min prior to ischemia and before reperfusion. The third group of rats was sham-operated and served as the control group. Gastric I/R injury increased serum lactate dehydrogenase level, vascular permeability of gastric mucosa (as indicated by Evans blue dye extravasation) and gastric content of inflammatory cytokine; tumor necrosis factor-alpha (TNF-alpha). Moreover, oxidative stress was increased as indicated by elevated lipid peroxides formation (measured as thiobarbituric acid reactive substances) and depleted reduced glutathione in gastric tissues. NF-kappaB translocation was also detected by electrophoretic mobility shift assay. Microscopically, gastric tissues subjected to I/R injury showed ulceration, hemorrhages, and neutrophil infiltration. Immunohistochemical studies of gastric sections revealed increased expression of p53 and Bcl-2 proteins. PDTC pretreatment reduced Evans blue extravasation, serum lactate dehydrogenase levels, gastric TNF-alpha levels, and thiobarbituric acid reactive substances content, and increased gastric glutathione content. Moreover, PDTC pretreatment abolished p53 expression and inhibited NF-kappaB translocation. Finally, histopathological changes were nearly restored by PDTC pretreatment. These results clearly demonstrate that NF-kappaB activation and pro-apoptotic protein p53 induction are involved in gastric I/R injury. PDTC protects against gastric I/R injury by an antioxidant, NF-kappaB inhibition, and by reduction of pro-apoptotic protein p53 expression, which seems to be downstream to NF-kappaB, thus promoting cell survival.

Ischemic preconditioning of remote organs attenuates gastric ischemia–reperfusion injury through involvement of prostaglandins and sensory nerves

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.

Neuroregulative mechanism of hypothalamic paraventricular nucleus on gastric ischemia–reperfusion injury in rats

A rat model of gastric ischemia–reperfusion injury (GI-RI) was established by clamping the celiac artery for 30 min and allowing reperfusion for 1 h, on which the regulatory effect of the paraventricular nucleus (PVN) and its neural mechanisms were investigated. The results were: 1. Electrical stimulation of the PVN obviously attenuated the GI-RI. Microinjection of L-glutamic acid into PVN produced an effect similar to that of PVN stimulation. 2. Electrolytic ablation of the PVN aggravated the GI-RI. 3. Nucleus tractus solitarius (NTS) ablation could eliminate the protective effect of electrical stimulation of PVN on GI-RI. 4. Hypophysectomy did not alter the effect of electrical stimulation of PVN. 5. Vagotomy or sympathectomy both could increase the effect of PVN stimulation on GI-RI. These results indicate that the PVN participates in the development of GI-RI as a specific area in the CNS, exerting protective effects on the GI-RI. The NTS and vagus and sympathetic nerve may be involved in the regulative mechanism of PVN on GI-RI, but the PVN mechanism here is independent of the PVN-hypophyseal pathway.

Effects of electrical stimulated hypothalamic paraventricular nucleus on gastric ischemia-reperfusion injury in rats

Effects of electrical stimulated hypothalamic paraventricular nucleus on gastric ischemia-reperfusion injury in rats

Involvement of reactive oxygen species and nitric oxide in gastric ischemia-reperfusion injury in rats: protective effect of tetrahydrobiopterin.

The purpose of this study was to examine whether tetrahydrobiopterin (BH4), a cofactor of nitric oxide (NO) synthase, attenuates gastric ischemia-reperfusion injury induced by clamping of the celiac artery. Gastric injury was assessed by a formation of gastric mucosal erosions. The gastric injury was observed at 30 and 60 min after reperfusion following 30-min ischemia and was reduced by superoxide dismutase (SOD), catalase, or NO synthase inhibitors. Therefore, reactive oxygen species (ROS) and NO seem to be implicated in the ischemia-reperfusion injury. Treatment with BH4 reduced the ischemia-reperfusion injury. Pretreatment with sepiapterin, a precursor of BH4, also reduced the ischemia-reperfusion injury with an increase in BH4 content in serum and stomach. Both the increase in BH4 content and the protective effect of sepiapterin were prevented of pretreatment with N-acetylserotonin, an inhibitor of BH4 synthesis. These results suggest that the increase in BH4 content may protect against gastric ischemia-reperfusion injury via reduction of ROS and/or NO toxicity. BH4 might be useful as a therapeutic agent for gastric ischemia-reperfusion injury.

P–326 - Involvement of reactive oxygen species and nitric oxide on gastric ischemia-reperfusion injury in rat: Protective effect of tetrahydrobiopterin.

P–326 - Involvement of reactive oxygen species and nitric oxide on gastric ischemia-reperfusion injury in rat: Protective effect of tetrahydrobiopterin.

Protection of local gastric ischemia-reperfusion injury by L-arginine in rat

Protection of local gastric ischemia-reperfusion injury by L-arginine in rat

Phosphoramidon, an endothelin converting enzyme inhibitor attenuates local gastric ischemia-reperfusion injury in rats

Recently increased production of endothelin-1 has been implicated in the pathogenesis of gastric ischemia-reperfusion injury. We have investigated the effects of endothelin converting enzyme inhibition on local gastric ischemia-reperfusion injury in rats by using two metalloprotease inhibitors, phosphoramidon and thiorphan. In presence of exogenous 0.15M HCI intragastrically, local ischemia was induced by the clamping of left gastric artery for 15 min and reperfusion was done for 30 min. In separate group of rats, phosphoramidon (10–60 mg kg ) or thiorphan (60 mg kg ) were given as i.v. bolus injection immediately before the induction of ischemia. Phosphoramidon dose dependently attenuated the macroscopic and microscopic mucosal injuries while thiorphan did not. These results indicate that phosphoramidon-sensitive endothelin converting enzyme activity is highly present in stomach and phosphoramidon, by inhibiting the conversion of big endothelin-1 to endothelin-1 attenuated the gastric mucosal damage in this model.

Gastric mucosal injury induced by local ischemia-reperfusion in rats. Role of endogenous endothelin-1 and free radical.

We investigated the role of an endogenous vasoconstrictor peptide endothelin-1 (ET-1) and free radicals in local gastric ischemia-reperfusion injury in rats. Local gastric ischemia was induced by clamping the left gastric artery for 15 min and reperfusion was done for 10-30 min in the presence of 150 mM exogenous HCl intragastrically. Local gastric ischemia and reperfusion resulted in significant macroscopic and microscopic gastric mucosal damage together with elevation of gastric tissue ET-1 concentration. Gastric tissue ET-1 was found to increase after 15 min of ischemia alone and also with 30 min of reperfusion. A novel nonpeptide endothelin receptor antagonist, bosentan, or a combination of radical scavengers (superoxide dismutase, catalase, and deferoxamine) both attenuated gastric mucosal injury. However, the greater protection observed with bosentan than with radical scavengers might reflect a preferential role of endothelin-1 in this type of injury.

Protection against gastric ischemia-reperfusion injury by nitric oxide generators.

Nitric oxide appears to play an important role in maintaining gastric mucosal integrity. This study aimed to investigate whether a nitric oxide donor (sodium nitroprusside) or stimulation of endogenous nitric oxide synthesis (with acetylcholine) protects against gastric ischemia-reperfusion injury. Rats were subjected to 30 min of ischemia followed by 15 min of reperfusion. Injury was assessed by quantitative histology. Intravenous sodium nitroprusside (50-75 micrograms/kg) or acetylcholine (10-25 micrograms/kg), immediately before reperfusion, significantly reduced the percentage of mucosal injury compared with controls. Inhibition of nitric oxide synthesis by topical application of 12.5 mg/kg NG-methyl-L-arginine before acetylcholine treatment, abolished the effects of acetylcholine. The protective effects of acetylcholine and sodium nitroprusside did not appear to be related to local vasodilation since neither drug improved gastric blood flow and infusion of a non-nitric oxide vasodilator (papaverine, 1 mg/kg), had no protective effect on reperfusion injury. Sodium nitroprusside (50 micrograms/kg) and acetylcholine (25 micrograms/kg) significantly reduced polymorphonuclear leukocyte infiltration and extravasation into the mucosa compared with controls. NG-Methyl-L-arginine pretreatment before acetylcholine abolished these effects. We conclude that nitric oxide generators significantly reduce mucosal injury following ischemia-reperfusion and that this may occur via a reduction in polymorphonuclear leukocyte infiltration into the mucosa.

Polymorphonuclear leukocyte infiltration into gastric mucosa after ischemia-reperfusion

Polymorphonuclear leukocytes (PMN) have been implicated in the pathogenesis of ischemia-reperfusion injury. The objective of this study was to investigate PMN infiltration and distribution within the gastric mucosa of rats subjected to 30 min gastric ischemia followed by reperfusion. Sections of mucosa were stained for PMN using an immunoperoxidase technique, and injury was assessed by quantitative histology. In control animals, there were 4 +/- 2 PMN/mm2 in the superficial and 9 +/- 4 PMN/mm2 in the deep mucosa. This increased significantly to 67 +/- 9 PMN/mm2 (P < 0.05) and 160 +/- 53 PMN/mm2 (P < 0.01) respectively at 15 min of reperfusion. The percentage of these PMN which were extravasated was 83 +/- 4% in the superficial mucosa and 82 +/- 4% in the deep mucosa (P < 0.001 compared with control levels of 0% in superficial and 10% in deep mucosa). Significant PMN infiltration occurred before full expression of mucosal injury and treatment of rats with anti-PMN antisera blocked reperfusion injury (treated 10.7 +/- 1.4% mucosa damaged, controls 33.5 +/- 2.4%; P < 0.001). Treatment with allopurinol (100 mg/kg) significantly reduced the number of infiltrating PMN (superficial 7 +/- 1/mm2, deep 16 +/- 2/mm2; P < 0.01) and the percentage of extravasating PMN (superficial 40 +/- 10%, deep 30 +/- 15%; P < 0.01) while also significantly reducing tissue injury (21.9 +/- 1.9% mucosa damaged, P < 0.01 compared with controls). We conclude that the immunoperoxidase staining provides a simple means of identifying PMN in histological sections. Furthermore, our results support a role for PMN in gastric ischemia-reperfusion injury.