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.     

Somatostatin increases the ratio between gastric mucosal blood flow and gastric acid and pepsin secretion in dogs

The effects of somatostatin on gastric mucosal blood flow (GMBF), acid secretion, and pepsin secretion were evaluated. Conscious gastric fistula dogs were used, with neutral red clearance as the method for estimating the mucosal blood flow. Somatostatin inhibited the pentagastrin- and bethanechol-stimulated gastric acid and pepsin secretion and resulted in an absolute decrease in mucosal blood flow. The ratios between GMBF and secretion (acid and pepsin) were increased during somatostatin infusion, which suggests a relative increase in mucosal blood flow and independent inhibition of gastric secretion. It may be concluded from this study that the acid- and pepsin-inhibitory effects of somatostatin are not mediated by changes in the GMBF.     

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     

Role of dorsal motor nucleus of vagus in gastric function and mucosal damage induced by ethanol in rats

Experimental evidence indicates that the autonomic nervous system, especially the cholinergic pathway, modulates the mucosal defensive mechanism and affects mucosal damage in the stomach. The present study investigated the role of the dorsal motor nucleus of vagus (DMV) in gastric function and its influences on ethanol-induced mucosal damage in pentobarbitone-anesthetized rats. Electrolytic lesion of the DMV as compared with sham operation and lesions of other brain areas, eg, nucleus reticular gigantocellularis and cuneate nucleus, reduced the basal gastric mucosal blood flow (GMBF) and also the blood flow after ethanol administration. The same operation did not affect the acid secretion either in the basal state or during the ethanol treatment period. Lesions at the caudal half of the DMV produced a bigger depression of GMBF when compared with lesion at the rostral half. In the sham-operated rats, ethanol induced severe hemorrhagic lesions in the gastric glandular mucosa, and this was significantly potentiated by lesions at the DMV, especially in the caudal half. The present findings indicate that acute DMV damage at the caudal half markedly affects the GMBF but not the acid secretion. The action on GMBF may contribute to the aggravation of ethanol-induced gastric damage in rats. These data reinforce the idea that the central vagal pathway, especially the caudal half of the DMV, plays a significant role in the modulation of GMBF, which in turn affects the integrity of gastric mucosal barrier.     

垂体后叶素对门脉高压性胃病胃粘膜灌注的影响

目的 探讨垂体后叶素对门脉高压性胃病（ＰＨＧ）大鼠胃粘膜血流量（ＧＭＢＦ）和血浆胰高粘素的影响。方法 部分结扎大鼠门脉主干２ｗｋ后,采用激光多普勒血流计（ＬＤＦ）测定大鼠ＧＭＢＦ,观察了垂体后叶素输注前和输注后３０ｍｉｎ ＧＭＢＦ,门脉压力（ＰＶＰ）的变化;测定了输注垂体后叶素３０ｍｉｎ后血浆胰高糖素的含量。结果 输注垂体后叶素１０ｍｉｎ ＰＨＧ大鼠的ＧＭＢＦ开始降低（Ｐ〈０．０５）,１５ｍｉｎ显     

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.     

Gastric functions in portal hypertension

This study investigated the effects of portal hypertension on gastric motor and secretory functions and the role of endothelin in rats. Control; sham-operated; endothelin-A receptor blocker, BQ 485 (1 µg/kg) -treated; portal hypertensive; and portal hypertension +, endothelin-A receptor blocker-treated rats were subjected to tests of gastric secretory, motor, and mucosal function studies as well as gastric wall polymorphonuclear infiltration. Portal hypertension was induced by partial portal vein ligation. Portal hypertension suppressed gastric acid and total fluid secretion and delayed gastric emptying. An increase in mucosal permeability and no alteration in gastric wall myeloperoxydase activity were observed. The effects of portal hypertension on gastric secretory, motor, and mucosal functions were reversed by treatment with endothelin-A receptor blocker, BQ-485. It is concluded that portal hypertension suppresses the gastric motor and secretory functions and endothelin plays an important role in the pathophysiology of gastric alterations associated with portal hypertension.     

The role of the vagus nerve in the protective action of acid inhibitors on ethanol-induced gastric mucosal damage in rats

The role of vagus in the actions of different acid inhibitors on ethanol-induced gastric damage and mucosal blood flow (GMBF) changes was studied in anaesthetized rats, using an ex vivo stomach chamber preparation. Subdiaphragmatic bilateral vagotomy decreased the basal gastric acid secretion and GMBF; it also intensified ethanol-evoked lesions in the glandular mucosa. Misoprostol, omeprazole and cimetidine produced a similar degree of reduction in acid output. Misoprostol given subcutaneously (s.c.) (50 micrograms/kg), or added to the incubation solution (12.5 micrograms) for 15 min, markedly prevented ethanol-induced lesion formation and reduction in GMBF. The reversing effect of s.c. injection of misoprostol on either lesion formation or on GMBF reduction was attenuated by vagotomy. Omeprazole protected against lesion formation only when present in the incubation solution (12.5 mg) of ex vivo chamber preparations of both vagus-intact and vagotomized animals, but the effect was significantly less in the latter group. The drug also prevented the depressive action of ethanol in vagus-intact animals. Cimetidine pretreatment (50 mg s.c. or 12.5 mg in incubation solution), however, did not modify the effects of ethanol on lesion formation and the GMBF. The findings indicate that the three different types of acid inhibitors exert different actions on ethanol-induced gastric mucosal damage, although they produced similar inhibition of acid output. Vagotomy lowers the GMBF and attenuates the antiulcer action of misoprostol and omeprazole, especially when the drugs are given by the parenteral route.     

Gastric mucosal blood flow and pepsin secretion in dogs--stimulation by 13-nle-motilin.

In response to graded doses of intravenous 13-norleucine-motilin (13-nle-motilin)--a synthetic analogue of motilin and biologically equivalent to the natural polypeptide-, gastric mucosal blood flow (GMBF) in canine vagally denervated fundic pouches was studied using the aminopyrine clearance technique. As 13-nle-motilin did not exert any detectable effect on gastric secretion of hydrogen ions, intraluminal instillation of 160 mM HCl was used to provide a pH gradient allowing aminopyrine to move into the pouch lumen. With increasing doses of 13-nle-motilin, GMBF increased to 148% of control values; pepsin secretion - due to augmented pepsin concentration - rose concomitantly. Enhanced pepsin secretion was not accompanied by an increase in cyclic 3',5'-adenosine monophosphate secretion.     

Monochloramine impairs mucosal blood flow response and healing of gastric lesions in rats: relation to capsaicin-sensitive sensory neurons

AIMS:We examined the effects of monochloramine (NH2Cl) on the gastric mucosal blood flow (GMBF) response and the healing of ethanol-induced gastric lesions in rats. METHODS: Rats fasted for 18 h were given the 99% ethanol p.o. for induction of gastric lesions, and were fed normally from 1 h later onwards. Monochloramine, at non-ulcerogenic doses (5 to approximately 20 mmol/L), was given p.o. twice daily for 7 days, starting 2 h after ethanol treatment. RESULTS: Gastric lesions caused by ethanol healed almost completely within 7 days with re-epithelialization. The repeated administration of NH2Cl significantly delayed the healing of ethanol-induced gastric lesions in a dose-dependent manner. The damaged mucosa showed a marked rise in H+ permeability, resulting in luminal acid loss, but this process was accompanied by an increase of mucosal blood flow. Monochloramine did not affect the increased mucosal H+ permeability observed in the stomach after damage by ethanol, but significantly inhibited the mucosal hyperemic response associated with luminal acid loss. Prior exposure of the mucosa to NH2Cl (20 mmol/L) did not affect the gastric hyperemic response caused by mucosal application of misoprostol (a prostaglandin E1 derivative) or NOR-3 (a nitric oxide donor), but totally attenuated the increase of GMBF in response to intragastric capsaicin. Impaired healing and GMBF responses were also observed in rats following chemical ablation of capsaicin-sensitive sensory neurons. CONCLUSIONS: These results suggest that NH2Cl impaired the healing of acute gastric mucosal lesions at low concentrations, and this action may be attributable, at least partly, to the impairment of gastric hyperemic response caused by the dysfunction of capsaicin-sensitive sensory neurons.     

Time course study on the action of 5-hydroxytryptamine on gastric secretion and mucosal blood flow and on ethanol-induced gastric mucosal damage in rats.

The effects of 5-hydroxytryptamine (5-HT; given i.p. in doses of 1 or 10 mg/kg) on gastric secretion and mucosal blood flow (GMBF) and on ethanol-induced gastric mucosal damage were studied in rats over a period of 30-450 min. The blood pressure was also examined, in relation to the changes in GMBF. 5-HT, 10 mg/kg, given 30 min before ethanol administration markedly worsened lesion formation and this potentiating action was present for a further 90 min; a significant protective effect was seen only at 450 min after 5-HT injection. The lower dose of 5-HT, 1 mg/kg, did not affect the severity of gastric damage. 5-HT (10 mg/kg) also decreased GMBF at 30 min after injection and this lasted up to the end of 120 min, but the depressive action of ethanol on GMBF was reversed at 450 min. The basal gastric secretory volume was depressed from 30 to 120 min but acid output fell from 75 to 120 min after the higher dose of 5-HT; this reduction of acid secretion was followed by an increase from 360 to 450 min. 5-HT decreased the mean blood pressure in a dose- and time-dependent manner. The heart rate was unaffected by either dose level of 5-HT. The present study not only demonstrates the ulcerogenic action of 5-HT but also the protective nature of the amine. The reduction in secretory volume and lesion formation, but not acid secretion, seems to be related to GMBF depression, whereas the protective action depends on the maintenance of GMBF.     

The role of serotonin in ethanol-induced gastric glandular damage in rats

The effects of serotonin (5-HT) or methysergide (a 5-HT antagonist), given intraperitoneally 30 min beforehand, on ethanol-induced mucosal injury and mucosal blood flow were studied in rats. 5-HT itself dose dependently decreased the gastric mucosal mucus content and induced gastric damage in conscious animals. It also worsened ethanol-induced lesion formation but not mucus depletion. Methysergide pretreatment only prevented the former action. In the ex vivo chamber preparation, 5-HT lowered the gastric mucosal blood flow and produced mucosal damage in unconscious animals. It also potentiated ethanol-induced gastric injury and 5-HT release. Methysergide significantly prevented lesion formation and 5-HT release in ethanol-treated rats. Ethanol decreased the gastric mucosal blood flow in the mucosa which had been preincubated with HCl. This depression of gastric mucosal blood flow was further reduced by 5-HT, but was reversed by methysergide. The lesion-potentiating or -protecting actions of 5-HT or methysergide, respectively, suggest that the amine is involved in gastric mucosal damage by ethanol in rats.     

褪黑激素对胃黏膜的保护作用及其机制

目的：探讨褪黑激素和血清素对鼠胃酒精性溃疡及黏膜血流的影响。方法：制备胃在体动物模型。分别皮下注入血清素及同容积生理盐水。用褪黑激素及同容积蒸馏水作为浸育液分别放入各组鼠的胃腔中。30min未毕毕胃黏膜血流后,采用40％的酒精作为浸育液分别放入各组鼠胃腔中,继续检测胃黏膜血流并测量胃黏膜损伤指数。结果：褪黑激素和血清素两者均不能损伤鼠胃黏膜,但血清素可降低胃黏膜血流,且与其剂理相关。褪黑激素可减轻由酒精引起的胃黏膜损伤和胃黏膜血流减少,而血清素可加重酒精引起的胃黏膜损伤和胃黏膜血流减少,但可被褪黑激素部分逆转。结论：胃黏膜的损伤与胃黏膜血流有关,但不是溃疡形成的唯一因素。因此,能拮抗血清的褪黑激素可作为在胃肠道作用的调节剂。     

Effects of Endoscopic Variceal Ligation on Portal Hypertensive Gastropathy and Gastric Mucosal Blood Flow

Objective: Portal hypertensive gastropathy (PHG) has been recognized recently as a potential cause of upper gastrointestinal tract bleeding and is associated with a change in gastric hemodynamic indices in cirrhotic patients with portal hypertension. Endoscopic variceal ligation (EVL) is the treatment of choice for esophageal varices. We investigated the early effect of EVL on PHG and gastric mucosal blood flow (GMBF).
Methods: We examined 35 cirrhotic patients who were treated by EVL. PHG was evaluated endoscopically and GMBF was measured by laser Doppler flowmetry before and 1 or 2 wk after EVL.
Results: After EVL, only two patients (5.7%) developed severe PHG, 6 (17.1%) developed mild PHG, and 27 (77.1%) showed no change in endoscopic appearance of PHG. In those patients who developed PHG, EVL significantly decreased GMBF at the corpus (   p < .05  ). However, no significant changes of GMBF at the corpus were noted after EVL in those patients who had no worsening of endoscopic features. EVL had no effect on GMBF at the antrum in any patients.
Conclusions: Endoscopic variceal ligation is safe and does not lead, at least within 1–2 wk, to worsening of gastropathy in most cases. Our finding that gastropathy developed in the presence of reduced GMBF may suggest that PHG develops as a result of congestion caused by blockade of gastric blood drainage rather than by hyperemia.     

Autoradiographic study of the regional distribution of gastric blood flow in portal hypertensive rats

This study measures regional gastric blood flow in portal hypertensive rats at three separate periods after portal vein ligation using quantitative autoradiography with 14C-labeled iodoantipyrine. The level of corpus mucosal blood flow was significantly reduced in 3-day portal vein-ligated animals compared with sham-operated control animals (30.4 +/- 2.3 vs. 47.1 +/- 5.6 ml/100 g.min). There was no significant difference in corpus mucosal blood flow between portal vein-ligated and sham-operated animals at 7- and 28-day periods, although the level of perfusion was higher in the 28-day portal vein-ligated group. There was no significant difference in antral mucosal or muscle blood flow between portal hypertensive and control animals at any of the study periods. We conclude that the acute period after portal vein ligation is associated with a reduced corpus mucosal microcirculation but that this effect is not sustained in portal hypertensive animals studied at later intervals after portal vein ligation.     

The effect of prostacyclin on the gastric mucosa in portal-hypertensive rats

BACKGROUND/AIMS: This study investigates the effect of prostacyclin, which is thought to be involved in the hemodynamic circulation, on the gastric mucosa of rats with portal hypertension. METHODOLOGY: Various gastric functions were evaluated in portal vein ligated rats after the intraperitoneal administration of either a placebo or prostacyclin for 7 days. RESULTS: The gastric mucosal damage induced by the instillation of 90% ethanol was significantly greater in the prostacyclin-treated group than in placebo-treated group. The portal pressure was similar in both groups. There was no significant difference between the two groups in plasma concentration of 6-keto-PGF1a (a stable metabolite of prostacyclin), whereas the mucosal content of 6-keto-PGF1a was significantly higher in the prostacyclin-treated group than in the placebo-treated group. Prostacyclin pretreatment significantly increased the gastric mucosal blood flow, estimated by laser-Doppler flowmetry, and the hemoglobin content of the gastric mucosa, measured by reflectance spectrophotometry, whereas the oxygen content remained unchanged. CONCLUSIONS: We speculate that the increased gastric mucosal perfusion induced by a high content of prostacyclin in the portal hypertensive gastric mucosa may play a role in the pathogenesis of ethanol-induced gastric mucosal damage.     

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。     

Endothelin and neonatal capsaicin regulate gastric resistance to injury in BDL rats

AIM: To investigate the relationship between primary afferent neurons, endothelin (ET) and the role of its receptors on ethanol-induced gastric damage in cirrhotic rats. METHODS: Cirrhosis and portal hypertension were induced in rats by bile duct ligation (BDL) while controls had a sham operation. The association between ET and afferent neurons on the gastric mucosa was evaluated by capsaicin treatment in newborn rats, the use of ET agonists or antagonists, gastric ET-1 and -3 mRNA and synthetic capacity. Ethanol-induced damage was assessed using ex vivo gastric chamber experiments.Gastric blood flow was measured by laser-Doppler flow-metry. RESULTS: ET-3 and an ETB receptor antagonist sig- nificantly reduced the extent of ethanol-induced gastric damage in BDL rats. Gastric ET-1 and -3 levels were 30% higher in BDL rats compared to control rats. Cap-saicin treatment restored the gastric resistance and blood flow responses to topical application of ethanol in BDL rats and ET-1 and -3 production to levels observed in controls. CONCLUSION: Our results suggest that the reduced resistance of the gastric mucosa of cirrhotic rats to ethanol-induced injury is a phenomenon modulated by ET through the ET B receptor and by sensory afferent neurons.     

Propranolol reduces ethanol-induced gastric mucosal damage in portal hypertensive rats

In a standardized rat model of portal hypertension, we investigated the effects of propranolol on alcohol-induced gastric mucosal damage. Portal hypertensive rats pretreated with 2 mg propranolol, compared with those receiving saline, had significantly reduced portal pressures (24 +/- 1 vs 32 +/- 1 cm saline), macroscopic mucosal damage (24 +/- 1 vs 39 +/- 4% of mucosa), and histologic deep necrosis (36 +/- 2 vs 61 +/- 4% of mucosal length). Increased dosage of propranolol to 4 mg did not produce any further reduction of portal pressure or mucosal damage. Central venous and systemic arterial pressures were not significantly altered by propranolol. The extent of mucosal damage correlated with levels of portal pressure (P less than 0.01) in portal hypertensive rats. Sham-operated normotensive rats had less macroscopic mucosal damage (26 +/- 4%) than portal hypertensive rats, and propranolol did not affect the extent of ethanol-induced damage or portal pressures in these animals. We conclude: (1) Propranolol is effective in reducing extent of ethanol-induced gastric mucosal damage in portal hypertensive rats, but not in sham-operated controls; (2) this effect correlates with reduction of portal pressure; and (3) our study supports the clinical impression that reducing portal pressure may be one approach for the prevention and therapy of gastric mucosal damage in portal hypertension.     

Effects of propranolol and sucralfate on ethanol-induced gastric mucosal damage in chronic portal hypertensive rats

In a rat model of chronic portal hypertension we studied ethanol-induced gastric mucosal damage and the effects of pretreatment by propranolol and sucralfate. Susceptibility to ethanol was increased in chronic portal hypertensive rats compared with sham-operated rats (55 +/- 8% vs. 25 +/- 4%). Both acute pretreatment (10 min) and chronic pretreatment (3 weeks) with propranolol reduced gastric mucosal injury induced by ethanol in portal hypertensive rats, compared with saline-treated rats. Acute and chronic pretreatment with propranolol had no protective effect in sham-operated rats. In portal hypertensive rats, sucralfate in two different doses (500 and 125 mg/kg) protected the gastric mucosa against ethanol-induced gastric injury compared with animals receiving saline (2 +/- 1% and 3 +/- 2% vs. 25 +/- 3%). Sucralfate at the higher dose did not reduce portal pressure in portal hypertensive rats. We conclude that: (1) chronic portal hypertension increases ethanol-induced gastric damage; (2) acute and chronic propranolol treatment reduces ethanol-induced gastric injury in portal hypertensive rats, probably by decreasing portal hypertension; (3) sucralfate has a cytoprotective effect in portal hypertensive rats without reducing portal pressure. These results suggest a potential application of sucralfate in patients otherwise treated by sclerotherapy.