Influence of NG‐nitro‐L‐arginine methyl ester and L‐arginine on gastric mucosal tolerant cytoprotection under stress

OBJECTIVE : To determine the role of endogenous nitric oxide (NO) in gastric mucosal tolerant cytoprotection under stress and its possible mechanism. METHODS : Sprague–Dawley rats were exposed to repeated water immersion and restraint stress (WRS), during which N^G‐nitro‐L ‐arginine methyl ester (L ‐NAME), a non‐selective NO synthase inhibitor, and L ‐arginine (L ‐Arg), a substrate for NO synthesis, were administered to inhibit or promote the synthesis of endogenous NO, respectively. Gastric mucosal blood flow (GMBF) was measured with an LDF‐3 Flowmeter (Electronic Instrument Factory of Nankai University, Tianjin, China), the NO level in the gastric mucosa was monitored by the Griess reaction and gastric mucosal lesions were evaluated using the ulcer index (UI). The relationships between changes in GMBF, UI and NO content in the gastric mucosa were analyzed by linear correlation analysis. RESULTS : Repeated WRS induced gastric mucosal tolerant cytoprotection and this was accompanied by increased GMBF and NO levels in the gastric mucosa. Inhibition of endogenous NO synthesis by L ‐NAME worsened mucosal lesions induced by single WRS and, after repeated WRS, the adaptive incremence in GMBF was abolished and the NO content in the gastric mucosa was significantly reduced. In contrast, enhancement of endogenous NO synthesis by L ‐Arg attenuated mucosal erosions caused by single WRS. After repeated WRS, GMBF and the NO content in the mucosa increased gradually. Mucosal lesions were negligible after rats were exposed to the fourth WRS. CONCLUSIONS : During the tolerant cytoprotection, GMBF, UI and the NO content showed regular changes and there were good relationships between them. L ‐NAME and L ‐Arg changed the levels of endogenous NO, which, accordingly, affected GMBF and the gastric tolerance. By regulating GMBF, endogenous NO may play an important role in the gastric mucosal tolerant cytoprotection under stress. Inhibition of the synthesis of NO delayed the induction of tolerant cytoprotection, whereas increased NO synthesis promoted cytoprotection.     

左旋精氨酸甲酯及左旋精氨酸对应激状态下胃黏膜耐受性细胞保护作用的影响

目的：探讨内源性一氧化氮（NO）在应激状态下胃黏膜耐受性细胞保护中的作用及其可能的机制。方法：以重复浸水束缚应激（WRS）制作动物模型,以左旋精氨酸甲酯（L－NAME）或左旋精氨酸（L－Arg）抑制或促进内源性NO的合成,动态检测胃黏膜血流量（GMBF）、溃疡指数（UI）、黏膜一化氮含量的变化。结果：重复应激后,实验对照组大鼠UI明显下降,同时GMBF上升,黏膜内NO含量增高;L－NAME使WWRS引起的胃黏膜损伤加重,消除了GMBF的递增趋势,黏膜NO含量下降;而L－Arg可减轻WRS造成的黏膜损伤,GMBF、黏膜NO含量增相应增加;GMBF、UI、黏膜NO含量变化之间有相关关系。结论：内源性NO通过调节GMBF而介导耐受性细胞保护作用,L－NAME抑制其合成,延缓这一作用,L－Arg增加其合成,促进该作用。     

Epalrestat prevents the decrease in gastric mucosal blood flow and protects the gastric mucosa in streptozotocin diabetic rats

We have recently reported that steady-state gastric mucosal blood flow (GMBF) is decreased in streptozotocin (STZ) diabetic rats, and that their GMBF response to burn-stress is impaired, probably via a nitric oxide (NO)-mediated mechanism. Accordingly, this study was designed to investigate the relation of aldose reductase (AR) and NO synthase to the regulation of GMBF during chronic hyperglycemia. STZ rats were treated with or without chronic oral administration of an AR inhibitor, epalrestat (EPA) and/or an NO synthase inhibitor, N-nitro-L-arginine methyl ester (L-NAME). GMBF was measured by laser-Doppler velocimetry (LDV). In the STZ rats, GMBF after a 24-h fasting period was decreased significantly 4 weeks after the onset of diabetes and this was accompanied by an increase in the gastric ulcer index (UI) (a measure of the length of gastric erosions and ulcers). Chronic oral administration of EPA to the STZ rats dose-dependently inhibited the increased UI and the decreased GMBF after the fasting stress, whereas chronic oral administration of L-NAME further increased the UI and further decreased the GMBF. EPA administered in combination with L-NAME to the STZ rats reduced the effects of L-NAME, but the effects did not reach significance. These results suggest that EPA protects the gastric mucosa of diabetic rats, by preventing the decrease in GMBF that is, at least in part, caused by NO-related mechanisms. (Received Mar. 3, 1998; accepted Aug. 28, 1998)     

善得定对门静脉高压性胃病大鼠胃粘膜灌注的影响

目的 观察善得定对门静脉高压性胃病（ｐｏｒｔａｌ ｈｙｐｅｒｔｅｎｓｉｖｅ ｇａｓｔｏｐａｔｈｙ,ＰＨＧ）大鼠胃粘膜血流最（ｇａｓｔｒｉｃ ｍｕｃｏｓａｌ ｂｌｏｏｄ ｆｏｗ,ＧＭＢＦ）的影响,并对其作用机制作初步探讨。方法 部分结扎大鼠门静脉主干２周后,观察善得定对ＰＨＧ大鼠全身血流动力学,ＧＭＢＦ,门静脉压力（ＰＶＰ）的影响,测定了输注善得定３０ｍｉｎ后ＰＨＧ大鼠血浆胰高糖素,血浆和胃粘膜ＮＯ     

l-arginine and endogenous nitric oxide protect the gastric mucosa from endothelin-1-induced gastric ulcers in rats

We have reported that endothelin-1 induces gastric ulcer characterized by a potent long-lasting vasoconstriction of the regional microvasculature. Nitric oxide synthesized froml-arginine has been shown to regulated gastric mucosal blood flow, and inhibition of its synthesis has been shown to delay the healing of gastric ulcers. We examined the effect of exogenousl-arginine and the inhibition of nitric oxide synthesis on the development of endothelin-1-induced gastric ulcers. In rats anesthetized with urethane, a continuous intravenous infusion ofl-ord-arginine (10 mg·kg^?1·min^?1) was followed, 15 min later, by a submucosal injection of endothelin-1 (200 pmol/kg) in the anterior wall of the gastric body. In another group, rats were intravenously pretreated with N^ω-nitro-l-arginine-methyl ester (1–10mg/kg), a nitric oxide synthesis inhibitor, and then injected with endothelin-1 (40 pmol/kg). Twenty-four h later,l-arginine, but notd-arginine, had significantly reduced the extent and the severity of the endothelin-1-induced ulcer (mucosal wall damage, 18.11 ± 4.79% and 88.14 ±7.06%, respectively; mean ± SD,P<0.001), and the nitric oxide synthesis inhibitor (10mg/kg) had increased the endothelin-1-induced mucosal damage (ulcer length, 3.8 ± 1.2 mm and 1.1 ± 0.2 mm, respectively,P<0.01). Continuous gastric mucosal blood flow measurements showed thatl-arginine antagonized the endothelin-1-induced vasoconstriction.l-arginine protected the gastric mucosa from the ulcerogenic action of endothelin-1 and antagonized its vasoconstrictive action. The inhibition of endogenous nitric oxide potentiated the ulcerogenic effect of endothelin-1 on rat gastric mucosa.     

内皮素，一氧化氮在内毒素血症大鼠胃粘膜损伤中的作用

目的：观察内皮素－1（ET－1）、一氧化氮（NO）在内毒素血症胃粘膜扣伤中的作用。方法：应用内毒素血症胃粘膜损伤模型分别观察血浆、胃粘膜中ET－1、NO含量变化,以及胃粘膜血流（GMBF）、胃粘膜损伤面积的变化。结果：内毒素血症时ET－1含量增加、NO含量减少,特异性内皮素受体ETAR阻滞剂（BQ123）、NO前体L－精氨酸（L－Arg）能减轻内毒素血症时胃粘膜损伤的程度。一氧化氮合酶阻滞剂N^G－硝基－L－精氨酸甲酯（L－NAME）加重了该模型胃粘膜的损伤。结论：内源性ET－1／NO失衡参与了内毒素血症时胃粘膜损伤病理过程。纠正内源性ET－1／NO失衡,通过改善了GMBF,减轻胃粘膜损伤。     

一氧化氮和前列腺素在门静脉高压性胃病大鼠胃粘膜灌注中的作用

目的 探讨一氧化氮（NO）和前列腺素在门静脉高压性胃病（PHG）大鼠胃粘膜灌注中的作用。方法 部分结扎大鼠门静脉主干2周后,采用中性红清除率法测定大鼠胃粘膜血流量（GMBF）,同时观察门静脉压力（PVP）的变化。结果 PHG组大鼠GMBF和PVP显著高于假手术组（t=3.431、3．312,P＜0．01）。低剂量的NO合成酶抑制剂L－硝基－精氨酸甲酯（L－NAME）呈剂量依赖性降低PHG大鼠GMBF,而对假手术组GMBF无明显影响;高剂量的L－NAME（12mg/kg)能非常显著降低PHG和假手术组大鼠GMBF。前列腺素环氧合酶抑制剂消炎痛能明显降低PHG组大鼠GMBF,而对假手术组GMBF无明显影响;预先给消炎痛处理后在假手术组大鼠中,静脉注射低剂量L－NAME（4mg/kg)前后GMBF无明显变化,高剂量L－NAME（12mg/kg)降低大鼠的GMBF与未用消炎痛处理组比无明显变化;预先给消炎痛处理后在PHG组大鼠中,L－NAME剂量（4mg/kg、12mg/kg)依赖性降低大鼠的GMBF与未用消炎痛处理组比无明显改变。结论 NO、前列腺素在调节PHG大鼠的GMBF起重要作用,但两者无协同作用。     

Colloidal bismuth subcitrate-induced changes on gastric mucosal hemodynamics in the rat: gastric mucosal blood flow after CBS treatment

The belief that blood flow plays a central role in cytoprotection and there being no data available, at present, regarding the possible action of Colloidal bismuth subcitrate (CBS-DENOL) on the gastric mucosal blood flow (GMBF), led us to investigate its influence on mucosal hemodynamics in the rat stomach. Measurements of GMBF were performed in 32 male Wistar rats, treated by either CBS or placebo in drinking water for a 3-wk period, by the use of a laser-Doppler flowmeter, at 14 defined points of the stomach. CBS treated animals revealed a highly statistically significant increase (P less than 0.0005, upaired t-test) of GMBF in comparison with the placebo treated. These findings lead us to suggest that CBS exerts its antiulcer action via the mechanism of increased gastric mucosal blood flow. Additionally the increased blood flow may be associated with the previous findings of increased synthesis of prostaglandins, gastric mucus and bicarbonate secretion by CBS.     

Reversal of the gastric effects of nicotine by nitric oxide donor treatment

Nicotine intensifies experimental gastric ulceration by reducing gastric mucosal blood flow (GMBF) and mucus. As both these parameters can be improved by nitric oxide (NO), we evaluated the impact of a NO donor in ethanol-induced gastric mucosal injury in rats administered nicotine. A nicotine solution or water was administered for 20 days to Sprague-Dawley rats. NO donor (isosorbide dinitrate) was given 60 and 10 min before preparation of ex vivo gastric chambers and exposure to ethanol. Chronic nicotine intake significantly reduced GMBF and gastric mucus content. Nicotine intensifies ethanol-induced gastric injury and short-term administration of NO donor failed to antagonize the ulcerogenic action from either nicotine or alcohol. In another study, rats drank nicotine solution for 20 days, after which the nicotine was withdrawn and replaced by water for 10 additional days. NO donor was provided during these last 10 days. The gastric effects of nicotine persisted for at least 10 days after nicotine was withdrawn but then these effects could be abolished by prolonged NO treatment. Nicotine reduces plasma nitrite level, but gastric mucosal MPO activity remained unchanged. Our data suggest that nicotine cessation plus a longer period of NO donor administration can completely abolish the gastric effects of nicotine.     

应激状态下大鼠胃黏膜组织中内皮素-1A受体mRNA的表达及其意义

应激性溃疡(SU)是危重疾病的常见严重并发症,其发生机制尚不清楚。研究表明内源性缩血管因子内皮素(ET)-1与SU密切相关,而关于其受体表达在SU发生中作用的研究尚少。目的:探讨ET-1A受体(ETAR)mRNA表达在SU发生中的作用和意义。方法:以冷束缚应激(CRS)制备大鼠胃溃疡模型,应激前和应激1 h、3 h、6 h、9 h、12 h后分别采用放射免疫测定、逆转录聚合酶链反应(RT-PCR)和斑点杂交等方法,动态检测血浆和胃黏膜组织中的ET-1和胃黏膜组织中的ETAR mRNA水平,同时检测胃黏膜血流量(GMBF)和溃疡指数(UI)等指标的变化情况。结果:与正常对照组相比,各应激组大鼠血浆和胃黏膜组织中的ET-1水平均显著升高(P<0.05),GMBF显著下降(P<0.01),UI显著增加(P<0.01);胃黏膜组织中的ET-1水平与UI呈显著正相关(r=0.98,P<0.01),与GMBF呈显著负相关(r=-0.89,P<0.05),而血浆ET-1水平与GMBF、UI相关性不显著(r=-0.61,0.43,P>0.05)。GMBF与UI呈显著负相关(r=-0.98,P<0.01)。RT-PCR和斑点杂交显示各应激组大鼠胃黏膜组织中ETAR mRNA的表达水平较正常对照组显著升高(P<0.01),并与胃黏膜组织中的ET-1水平和UI呈显著正相关(r=0.93,0.95,P<0.01)。结论:在CRS诱发大鼠急性胃黏膜损伤的过程中,胃黏膜组织可显著增加ET-1的合成分泌和ETAR mRNA的     

Altered vascular response to acetylcholine in conditions of endothelial damage in the isolated perfused rat stomach

To examine the mechanism of stress ulcers and the relation between endothelium derived relaxing factor (EDRF)/NO and gastric mucosal blood flow (GMBF), we used an isolated perfused rat stomach model and studied the effects of an autonomic nerve activator, nitric oxide synthase (NOS) synthesis, and an EDRF/NO inhibitor on gastric blood circulation. Rats were divided into four groups according to pretreatment: (1) control; (2) those given gossypol, a drug provoking endothelial cell damage; (3) those given L-N-monomethylarginine (L-NMMA), a specific inhibitor of EDRF/NO; and (4) those subjected to water-immersion stress. Using this model we collected the perfusion fluid from the portal vein at various time points. After administration of acetylcholine, the perfusion flow increased in the control group, but perfusion flow showed no change in the L-NMMA group. On the other hand, the perfusion flow decreased in the gossypol and water-immersion stress groups. The perfusion fluid from the control group contained cGMP, but this substance was absent in the perfusion fluid of the other experimental groups. We considered that increased cGMP in the fluid came from endothelial cells. We presume that the presence of EDRF/NO is essential for the control of GMBF and that from the viewpoint of gastric ulcers, the lack of EDRF/NO may be an important factor in the decrease of GMBF in the early stages of water-immersion stress. Received: November 9, 1998 / Accepted: July 23, 1999     

Reduced gastric acid production in burn shock period and its significance in the prevention and treatment of acute gastric mucosal lesions

AIM To investigate the changes of gastric acid production and its mechanism in shock period of severe burn in rats.METHODS A rat model with 30% TBSA fullthickness burn injury was employed and the gastric acid production, together with gastric mucosal blood flow (GMBF) and energy charge ( EC ) were measured serially within 48h postburn.RESULTS The gastric acid production in the acute shock period was markedly inhibited after severe burn injury. At the 3rd h postburn, the gastric juice volume, total acidity and acid output were already significantly decreased (P＜0.01), and reached the lowest point,0.63mL/L ± 0.20mL/L, 10.81mmol/L ±2.58mmol/L and 2.23 mmol/h ± 0.73mmol/h respectively, at the 12th h postburn. Although restored to some degree 24 h after thermal injury, the variables above were still statistically lower, compared with those of control animals at the 48th h postburn. The GMBF and EC were also significantly reduced after severe burns, consistent with the trend of gastric acid production changes.CONCLUSION Gastric acid production, as well as GMBF and EC was predominantly decreased in the early postburn stage, suggesting that gastric mucosal ischemia and hypoxia with resultant disturbance in energy metabolism, but not gastric acid proper, might be the decisive factor in the pathogenesis of AGML after thermal injury, and that the preventive use of anti-acid drugs during burn shock period was unreasonable in some respects. Therefore,taking effective measures to improve gastric mucosal blood perfusion as early as possible postburn might be more preferable for the AGML prevention and treatment.     

Effect of Biliary Cirrhosis on Neurogenic Relaxation of Rat Gastric Fundus and Anococcygeus Muscle: Role of Nitric Oxide Pathway

Background

Cirrhosis, associated with a host of hemodynamic abnormalities, could affect the gastrointestinal (GI) tract motility. On the other hand, the nonadrenergic noncholinergic (NANC) neurotransmission has been shown to play a pivotal role in GI tract motility and has been linked with release of nitric oxide (NO) on electrical stimulation. In this study, we investigated the effect of biliary cirrhosis on the neurogenic relaxation of rat gastric fundus and anococcygeus muscle and also the possible role of nitric oxide system in this manner.

Methods

Isolated gastric fundus and anococcygeus strips of sham-operated and biliary cirrhotic (4 weeks after bile duct ligation) rats were mounted under tension in a standard organ bath. Electrical stimulation was applied to obtain NANC-mediated relaxations in precontracted gastric fundus and anococcygeus muscle. The neurogenic relaxations were examined in the presence of different doses of NO synthase inhibitor, N ^w-Nitro-l-Arginine Methyl Ester (l-NAME). The concentration-dependent relaxant responses to the NO donor sodium nitroprusside were also evaluated.

Results

The neurogenic relaxation of both gastric fundus and anococcygeus muscle was significantly (P < 0.001) increased in cirrhotic animals. l-NAME (0.03–1,000 µM) inhibited relaxations in both groups in a dose-dependent manner (P < 0.001), but cirrhotic groups were more resistant to the inhibitory effects of l-NAME (P < 0.01). Sodium nitroprusside-mediated relaxations were similar in two groups.

Conclusions

This study for the first time demonstrated that cirrhosis increases the NO-mediated neurogenic relaxation of both rat gastric fundus and anococcygeus muscle, suggesting a crucial role for the neurogenic NO in the pathophysiology of disturbed GI motility in cirrhosis.     

The influence of acute or chronic nicotine treatment on ethanol-induced gastric mucosal damage in rats

The influences of acute or chronic nicotine pretreatment on ethanol-induced changes on gastric secretion, mucosal blood flow (GMBF), and glandular mucosal damage were studied in anesthetized rats. Ethanol administration decreased gastric acid secretion and GMBF, which were accompanied by a marked increase in gastric mucosal damage. Acute nicotine incubation 2 or 4 mg dose-dependently elevated both the titratable acid in the luminal solution and the gastric secretory volume; it also prevented the depressive action on GMBF and gastric mucosal damage in ethanol-treated animals. Chronic nicotine treatment for 10 days reduced the inhibitory action of ethanol on gastric acid secretion; the higher dose (25 micrograms/ml drinking water) potentiated the decrease of GMBF and the ulcerogenic property of ethanol. However, chronic treatment with the lower dose (5 micrograms/ml drinking water) had the opposite effects; it also markedly increased the gastric secretory volume. It is concluded that acute nicotine pretreatment elevates, whereas chronic nicotine pretreatment differentially affects GMBF. These effects could account for their protective or preventive actions on ethanol ulceration. The increase in nonacid gastric secretory volume by nicotine could partially explain its antiulcer effect. Furthermore, the acid secretory state of the stomach appears unrelated to the ulcerogenic property of ethanol.     

Alterations in l-arginine and inflammatory markers in type 2 diabetic patients with and without microalbuminuria

Low-grade inflammation is closely involved in the pathogenesis of type 2 diabetes and associated micro- and macrovascular complications. The nitric oxide (NO) precursor l-arginine, is relevant to diverse pathological conditions including type 2 diabetes and its complications. High sensitive-CRP (hs-CRP), neopterin and arginine levels were measured in 46 normoalbuminuric, 45 microalbuminuric type 2 diabetics and in 32 healthy controls in order to assess the relationship between markers of inflammation and l-arginine. Hs-CRP concentrations were higher in microalbuminuric diabetic patients compared to normoalbuminuric patients and controls. Diabetics had higher serum and urine neopterin levels than controls. Urine neopterin and l-arginine levels differed significantly among diabetic patients with and without microalbuminuria. There were significant positive correlations between hs-CRP and BMI in healthy controls and diabetics with and without microalbuminuria. In microalbuminuric diabetics, hs-CRP correlated with microalbuminuria (MAU). Significant predictors for the development of microalbuminuria were higher postprandial glucose levels, lower creatinine clearance and lower serum l-arginine levels. Assessment of early markers of inflammation and endothelial function, such as neopterin and NO precursor l-arginine, may help to predict incipient nephropathy more accurately in type 2 diabetic patients.     

Protective effect of omeprazole on gastric mucosal of cirrhotic portal hypertension rats

Objective:To observe the protective effect of omeprazole on gastric mucosal of cirrhotic portal hypertension rats.Methods:All rats were randomly divided into normal control group,cirrhosis and treatment group.Thioacetamide was used to establish rat model of cirrhotic portal hypertension.The necrotic tissue of gastric mucosa ulcer focus,degree of neutrophils infiltration at the ulcer margin,portal pressure,portal venous flow,abdominal aortic pressure,abdominal aortic blood flow at front end,gastric mucosal blood flow(GMBF),glycoprotein(GP)of gastric mucosa,basal acid secretion,H' back-diffusion,gastric mucosal damage index,NO,prostaglandin E_2(PGE_2) and tumor necrosis factor-α(TNF-α) were determined respectively,and the pathological changes of gastric mucosa were also observed by microscope.Results:Compared with cirrhosis group and the control group,the ulcer bottom necrotic material,gastric neutrophil infiltration and UI of the treatment group were all decreased significantly(P0.01),GMBF value,GP values,serum NO,PGE_2,TNF- a were all significantly increased.Conclusions:Omeprazole has an important protective effect on gastric mucosal and it can increase gastric mucosal blood flow and related to many factors.     

L-citrulline Prevents Alveolar and Vascular Derangement in a Rat Model of Moderate Hyperoxia-induced Lung Injury

Background

Moderate normobaric hyperoxia causes alveolar and vascular lung derangement in the newborn rat. Endogenous nitric oxide (NO), which promotes lung growth, is produced from the metabolism of l-arginine to l-citrulline in endothelial cells. We investigated whether administering l-citrulline by raising the serum levels of l-arginine and enhancing NO endogenous synthesis attenuates moderate hyperoxia-induced lung injury.

Methods

Newborn rats were exposed to FiO₂?=?0.6 or room air for 14?days to induce lung derangement and then were administered l-citrulline or a vehicle (sham). Lung histopathology was studied with morphometric features. Lung tissues and bronchoalveolar lavage fluid (BALF) were collected for analysis. Lung vascular endothelial growth factor (VEGF), nitric oxide synthase (eNOS), and matrix metalloproteinase 2 (MMP2) gene and protein expressions were assessed.

Results

Serum l-arginine rose in the L-citr?+?hyperoxia group (p?=?0.05), as well as the Von Willebrand factor stained vessels count (p?=?0.0008). Lung VEGF immune staining, localized on endothelial cells, was weaker in the sections under hyperoxia than the l-citr?+?hyperoxia and room air groups. This pattern was comparable with the VEGF gene and protein expression profiles. Mean alveolar size increased in the untreated hyperoxia and sham-treated groups compared with the groups reared in room air or treated with l-citrulline under exposure to hyperoxia (p?=?0.0001). Lung VEGF and eNOS increased in the l-citrulline-treated rats, though this treatment did not change MMP2 gene expression but regulated the MMP2 active protein, which rose in BALF (p?=?0.003).

Conclusions

We conclude that administering l-citrulline proved effective in improving alveolar and vascular growth in a model of oxygen-induced pulmonary damage, suggesting better lung growth and matrix regulation than in untreated groups.     

GABAergic Mechanisms of Gastroprotection in the Rat: Role of Sensory Neurons, Prostaglandins, and Nitric Oxide

gamma-Aminobutyric acid (GABA) is a neurotransmitter found in both the central and the peripheral nervous systems including the gastrointestinal tract. The aims of the present studies were to examine mechanisms by which GABA exerts gastroprotective effects against ethanol- and water-restraint stress (WRS)-induced gastric mucosal injury in the rat. GABA, administered intragastrically (400 mg/kg), induced gastroprotection against ethanol and WRS by activating gastric sensory neurons to release calcitonin gene-related peptide (CGRP) and promote nitric oxide (NO) synthesis and release. Furthermore, these protective effects of GABA were associated with an increase in gastric mucosal blood flow (GMBF) that was dependent on sensory neuron and NO systems. GABA-mediated protection involved GABAA receptor activation and prostaglandin generation. In conclusion, intraluminal GABA protects the stomach against ethanol- and WRS-induced injury by mechanisms which involve sensory neuron/CGRP/NO pathways and increases in GMBF and prostaglandin generation.     

Intracisternal thyrotropin-releasing hormone-induced vagally mediated gastric protection against ethanol lesions: Central and peripheral mechanisms

Abstract The vagus is involved in mediating gastric cytoprotection and adaptive cytoprotection. However, the central and peripheral mechanisms through which the vagus expresses its action are still poorly known. Medullary thyrotropin-releasing hormone (TRH) plays an important role in the vagal regulation of gastric function. The stable TRH analogue, RX 77368, micro-injected into the cisterna magna or the dorsal motor nucleus (DMN) of the vagus at a dose that did not influence gastric acid secretion prevented gastric injury induced by intragastric administration of 60% ethanol in conscious or urethane-anaesthetized rats. The cytoprotective action of TRH is mediated through vagal cholinergic release of prostaglandin E₂ (PGE₂). Prostaglandin E₂ action is unrelated to changes in gastric mucosal blood flow (GMBF). In addition, other peripheral mechanisms involve calcitonin gene-related peptide (CGRP) contained in capsaicin sensitive afferent fibres and nitric oxide, both of which mediate the associated increase in GMBF induced by intracisternal injection of RX 77368. These data indicate that medullary TRH induces vagally mediated gastric protection against ethanol lesions. Its action is expressed through the muscarinic dependent release of PGE₂ and nitric oxide, and efferent function of capsaicin-sensitive afferent fibres releasing CGRP.