Neural control of gastric mucosal blood flow in the rat.

This study was designed to determine (1) whether sympathetic nerve stimulation reduces gastric mucosal blood flow through the opening of submucosal arteriovenous anastomoses ("shunts"); and (2) whether parasympathetic nerve stimulation increases gastric mucosal blood flow through a direct effect on vascular smooth muscle as well as through metabolic factors secondary to increased acid secretion. An in vivo microscopy technique for the direct visualization of the rat gastric microcirculation was employed. Stimulation of the splanchnic nerve for 3 min caused an initial constriction of submucosal arterioles followed by escape (dilation during continued splanchnic stimulation) in all rats. No arteriovenous anastomoses were seen either in the resting state or during nerve stimulation. Mucosal studies with splanchnic stimulation revealed an initial progressive slowing of flow in the capillaries, followed by escape (partial return of flow). There were no significant differences between the times to maximum initial circulatory change in the submucosa and mucosa, and between the times to maximum escape in the submucosa and mucosa. These findings indicate that, in the rat, sympathetic stimulation decreases mucosal blood flow through a constricting effect on the supplying submucosal arterioles and not through the opening of "shunts". In studies with vagal stimulation, the submucosal arterioles dilated within 10 sec of beginning stimulation in 45 of 51 observations (P less than 0.001) and decreased in diameter within 10 sec of cessation of stimulation in 45 of 51 observations (P less than 0.001). The immediate dilation with stimulation and constriction with cessation of stimulation suggests a direct vasodilator effect of vagal stimulation on the gastric submucosal arterioles.     

Spatial heterogeneity of mucosal blood flow during ischemia-reperfusion injury of rat stomach investigated by laser Doppler perfusion imaging

Spatial alterations in blood flow during the development of mucosal injury induced by ischemia-reperfusion in rats were determined with a two-dimensional laser Doppler tissue perfusion imager. The rats were anesthetized with pentobarbital, and the stomach was exteriorized on a stage; the mucosa was then sequentially scanned. The mucosa was constantly superfused with 0.1N HCl in physiological saline. Systemic arterial pressure was continuously monitored and blood was stepwisely withdrawn from the femoral artery by 20-mmHg stage and then maintained at 20 mmHg for 20 min. The shed blood was reinfused and the stomach was removed 30 min later. Under control conditions, the average perfusion of the forestomach was usually greater than that in the glandular stomach. When systemic blood pressure was stepwisely decreased, the extent of decrease in the mucosal blood perfusion unit was always greater than that in systemic blood pressure, but mucosal perfusion appeared to be uniformly decreased throughout the stomach. Ten min after reperfusion, a hypoperfused area began to appear in the corpus near the greater curvature, and this area subsequently increased. The area of ulcer formation corresponded with the hypoperfused area in the gastric mucosa 30 min after reperfusion. Pretreatment with CV-6209, a platelet-activating factor antagonist, significantly attenuated the hypoperfusion induced by reperfusion and also prevented gastric mucosal damage. Our results suggest that hypoperfusion in the mucosal microcirculation is indeed an important factor contributing to the localized occurrence of gastric mucosal lesions and that the laser Doppler perfusion imager is useful for the detection of local hypoperfused areas in the gastric mucosa.     

Vasoactive agents and the gastric microcirculation

The primary flow regulating mechanism in the gastric microcirculation of the rat was investigated using an in vivo microscopic technique. The effect of different vasoactive agents on the reactivity of submucosal and mucosal vessels to topically applied epinephrine was observed. Topically administered acetylcholine, histamine, serotonin, and compound $\text{48}\text{80}$ inhibited epinephrine induced vasoconstriction of small arterioles in the submucosa. Inhibition by compound $\text{48}\text{80}$ was associated with submucosal mast cell degranulation. Much larger doses of epinephrine (180 times that required for submucosal effects) applied to the mucosa resulted in slowing of flow and finally blanching but not constriction of mucosal vessels. The latter findings suggest that epinephrine diffused through the mucosa to constrict supplying arterioles in the submucosal plexus. Conclusions: (1) regulation of gastric mucosal blood flow is primarily via vasomotor effects on submucosal arterioles and not on mucosal microvessels; (2) no mucosal or submucosal arteriovenous anastomoses were seen; and (3) submucosal mast cells, through release of vasodilator amines, may modulate sympathetic vasoconstriction and thus may play a role in the local regulation of blood flow.     

Effect of aspirin plus hydrochloric acid on the gastric mucosal microcirculation

The effect of topically applied aspirin or HCl, or both, on gastric mucosal blood flow was studied by in vivo microscopy in the rat. Ten minutes after the topical application of 20 mM aspirin in 50 mM HCl, red blood cell flow ceased and red blood cells were no longer present in the superficial mucosal microvessels in 76.8% +/- 7.7% of the microscopic field. Hydrochloric acid (50 mM) alone caused this effect in only 12.8% +/- 12.8% of the field, whereas 20 mM aspirin alone had no effect. During this microcirculatory change, white thrombi were observed flowing through mucosal microvessels. Later, mucosal hemorrhages developed in areas where flow had ceased. Study of the submucosal microcirculation suggested that high concentrations of HCl are responsible for thrombus formation and low concentrations of HCl for submucosal arteriolar constriction. These results suggest that aspirin-induced acid back-diffusion causes thrombus formation in mucosal microvessels and submucosal arteriolar constriction. These microcirculatory changes might play a causative role in the cessation of mucosal blood flow, mucosal injury, and focal hemorrhage.     

Role of endothelin-1 in repeated electrical stimulation-induced microcirculatory disturbance and mucosal damage in rat stomach

The aim of the present study was to clarify the involvement of endogenous endothelin in the pathogenesis of gastric mucosal damage. The rat stomach was exposed and repeated electrical stimulation (RES) was applied to the small arterial wall close to the lesser curvature. Significant mucosal haemorrhagic lesions (ulcer and erosion) were noted within 30 min after RES. Intravital microscopic observations revealed that an arteriolar constriction occurred in the submucosal layer of the rat stomach approximately 5 min after the completion of RES. Following the arteriolar constriction, the mucosal blood flow of the rat stomach, which was monitored by using a laser Doppler velocimeter, decreased to approximately 30% of the control value. The plasma immunoreactive endothelin-1 level in the regional blood of the stomach was significantly increased immediately after RES preceding the decrease in mucosal blood flow. Immunohistochemical studies revealed that endothelin-1 and big-endothelin-1 were detectable in the arteriolar endothelium around the muscularis mucosa, supporting the involvement of endothelin-1 in RES-induced mucosal ischaemia. In addition, BQ-123, a specific antagonist of the endothelin A (ET_A) receptor, attenuated the reduction of blood flow and the development of haemorrhagic lesions observed in gastric mucosa subjected to RES. The results of the present study suggest that an excessive production of endothelin-1 in the arteriolar endothelium leads to microvascular derangements accompanied by haemorrhagic alterations of the gastric mucosa.     

Three-dimensional view of the vascular structure of the lower esophagus in clinical portal hypertension

The venous anatomy of the lower esophagus and upper stomach was studied in nine patients with portal hypertension and in five without, following infusion of a silicon rubber compound into vessels of the excised organs within whole tissues made transparent with methyl salicylate. Four venous channels were identified in normal tissues: intraepithelial, subepithelial superficial, deep submucosal and adventitial veins. In portal hypertensive patients, giant esophageal varices formed 2 to 3 cm above the esophagogastric junction fused with numerous superficial and deep submucosal veins. Gastric varices were present in the submucosa where the left gastric venous branch penetrated the gastric wall 2 cm below the esophagogastric junction. The lower esophageal varices were classified into two types of vascular structure: palisading type in five and bar type in four. The palisading type had dilated intraepithelial channels and numerous small superficial collateral veins extending in a longitudinal arrangement. The bar type had triply dilated subepithelial superficial veins and deep submucosal veins which eroded the epithelium, and the gastric varices were present in the latter type. Our study provides evidence of the three-dimensional vascular structure of the lower esophageal varices without the necessity for tissue dissection.     

Early microcirculatory stasis in acute gastric mucosal injury in the rat and prevention by 16,16-dimethyl prostaglandin E2 or sodium thiosulfate

We used in vivo microscopy and laser-Doppler velocimetry to examine the effects on the gastric mucosal microcirculation and in gastric mucosal blood flow of agents that induce acute gastric mucosal damage. In vivo microscopic observation of superficial mucosal capillaries revealed vascular stasis within a mean of 54, 81, or 61 s after 100% ethanol, 0.6 N HCl, or 0.2 N NaOH, with the subsequent development of hemorrhagic mucosal lesions. Mucosal blood flow estimated by laser-Doppler velocimetry decreased by 30% at 5 min after luminal application of 100% ethanol, and decreased further to about 40% of basal levels by 15 min. The decreased mucosal blood flow 15 min after application of 50% ethanol correlated with the extent of hemorrhagic mucosal lesions. Examination of the submucosal vessels that supply and drain the mucosa showed moderate dilation of small arterioles 1, 3, and 6 min after exposure to 100% ethanol but there were no consistent changes in venules. Mild vasoconstriction of small- and medium-sized venules could be detected 6, 10, and 15 min after NaOH but not after exposure to HCl. Pretreatment with 16,16-dimethyl prostaglandin E2 or sodium thiosulfate before exposure of the mucosa to ethanol prevented capillary stasis, maintained mucosal blood flow, and prevented the development of hemorrhagic gastric mucosal lesions. Topical mucosal application of 16,16-dimethyl prostaglandin E2 decreased, whereas topical exposure to sodium thiosulfate increased gastric mucosal blood flow, indicating that change in blood flow per se is an unlikely mediator of protection.     

Chronic nicotine intake causes vascular dysregulation in the rat gastric mucosa.

Chronic cigarette smoking has adverse effects on peptic ulcer disease because the healing of ulcers is delayed and the incidence of relapses is enhanced. Short term intake of nicotine induces vascular damage in the rat gastric mucosa, but the pathophysiological mechanisms of nicotine's action in the stomach are largely unknown. In this study rats were treated with nicotine, added to their drinking water, for 50 days. They were then anaesthetised and their stomachs perfused with acidified acetylsalicylic acid (ASA). Chronic nicotine treatment failed to change the effects of acidified ASA to induce gastric mucosal acid back diffusion, haemorrhagic damage and bleeding. Basal blood flow in the gastric mucosa was also unchanged by chronic nicotine intake, whereas the mucosal hyperaemia evoked by ASA induced acid back diffusion was averted. The concentrations of sulfidoleukotrienes were significantly augmented in the gastric wall of nicotine treated rats. These data show that chronic nicotine intake causes dysregulation of the gastric microcirculation, an effect that is associated with biochemical changes in the stomach. This study thus substantiates the adverse effects of smoking on gastric mucosal pathophysiology. These data suggest that inappropriate regulation of gastric mucosal blood flow inhibits recovery from gastric mucosal injury in smokers.     

Morphology of gastric microcirculation in cirrhosis

Morphologic alterations in the gastric microcirculation in cirrhosis were investigated following infusion of a silicone rubber compound into vessels of the excised stomach which was then cleared with methyl salicylate. In cirrhosis, arteriovenous anastomoses 15 to 50 micron in diameter were present in 5 of 10 patients; spiral arterioles were less than one-tenth as numerous as in stomachs from noncirrhotic patients. The arterioles mainly had a straight pattern and precapillaries, capillaries, and submucosal and subserosal veins were dilated in cirrhotics (p less than 0.05). The number of arteriovenous anastomoses was unrelated to the degree of vascular dilatation and the number of spiral arterioles. These morphological alterations are consistent with decreased arteriovenous flow resistance in the stomach of cirrhotic patients.     

Is there an antral-body portal system in the stomach?

The direction of blood flow from the gastric mucosa of the antrum of the rat stomach has been studied using the isotope Rb86Cl. In a series of five experiments radioactivity has been shown to be transported via the blood stream from the antrum to the parietal cell mass without passing through the general circulation first. It is suggested that a 'portal' or direct transport system from antral mucosa to the body of the stomach exists.     

Laparotomy stimulates an endogenous gastric mucosal protective mechanism in the rat. A microcirculatory and morphologic study of ethanol injury

In vivo microscopy in the anesthetized rat unexpectedly revealed that the topical application of 75% ethanol to the gastric mucosa had no effect on the mucosal microcirculation. If, however, the synthesis of endogenous prostaglandin was inhibited by indomethacin, the topical application of 75% ethanol resulted in complete superficial mucosal microcirculatory stasis in the majority of rats. In indomethacin-pretreated rats, Rioprostil, a synthetic prostaglandin E1 analogue, reversed this effect of topical ethanol. The degree of ethanol-induced histologic gastric mucosal damage was inversely correlated with time to complete stasis. Ethanol injury studies under various conditions revealed that laparotomy stimulated a gastric protective mechanism that persisted for between 1 and 2 h and that was blocked by indomethacin. In conclusion, (a) laparotomy stimulates a gastric mucosal protective mechanism that probably is mediated by prostaglandin synthesis, and (b) cessation of mucosal blood flow appears to be an important early step in ethanol-induced gastric mucosal injury, and maintenance of mucosal blood flow by endogenous or exogenous prostaglandin may play a major role in prostaglandin protection.     

Afferent nerve-mediated protection against deep mucosal damage in the rat stomach

Intragastric capsaicin protects against ethanol-induced gross mucosal lesion formation by stimulation of afferent nerve endings in the rat stomach. The aims of the present study were to examine histologically the protective effect of capsaicin and to test whether this effect is related to changes in mucosal eicosanoid formation and mucosal blood flow. Intragastric capsaicin (160 microM) significantly reduced gross mucosal lesion formation induced by 25% ethanol. Light microscopy revealed that the depth of erosions was attenuated likewise. However, capsaicin did not prevent ethanol from causing superficial damage to the mucosa as observed by light and scanning electron microscopy. The protective action of capsaicin against ethanol remained unchanged by a dose of indomethacin that reduced the ex vivo formation of prostaglandin E2 and 6-oxo-prostaglandin F1 alpha in the gastric mucosa by about 90%. Capsaicin alone did not affect the ex vivo formation of these prostaglandins and of leukotriene C4. Intragastric capsaicin (160 microM) enhanced gastric mucosal blood flow by 89% as measured by the hydrogen gas clearance technique. This effect was also observed when capsaicin was administered together with 25% ethanol. These data indicate that afferent nerve stimulation by intragastric capsaicin protects against deep mucosal damage in response to ethanol, an effect that seems related to an increase in mucosal blood flow but not to eicosanoid formation.     

Microcirculatory stasis precedes tissue necrosis in ethanol-induced gastric mucosal injury in the rat

The relation of blood flow stasis to the development of unequivocal histologic necrosis (loss of parietal cells from the column of contiguous cells) in ethanol-induced gastric mucosal injury was studied in anesthetized rats. The most rapid vascular change that occurred when the gastric mucosa was exposed to 100% ethanol was a severe segmental constriction of the large submucosal venules. At 22 sec, the average venular diameter was 52.2±6.0% of the original one. This was followed by complete superficial mucosal blood flow stasis at 49±4 sec and appearance of histologic evidence of necrosis in one of seven rats at 2.5 min, four of six rats at 10 min, and seven of seven rats at 60 min. We conclude that in ethanol-induced gastric mucosal injury, submucosal venular constriction occurs first, followed by cessation of mucosal blood flow to be followed later on with histologic evidence of necrosis.     

Direct observation of microcirculation of the basal region of rat gastric mucosa

We modified and improved techniques for the intravital microscopic observation of the rat gastric microcirculation. The stomach of anesthetized rats was cut along the greater curvature, and the posterior wall of the glandular stomach was fixed in a chamber with the serosal side up and perfused with warmed Tyrode's solution. A portion of the muscularis externa was resected with the serosa to make an observation window. Vascular casts were studied histologically after the injection of Monastral blue B gelatin solution. Vascular casts revealed that most of the microvasculature observed in the window was not located in the submucosa, but in the basal part of the mucosa. Microscopic observation showed that the basal mucosal arterioles branched to form the mucosal capillaries, and the collecting venules from the mucosal surface were seen in cross-sections to drain into the venules located in the basal mucosa, without penetrating the muscularis mucosae. Topical application of acetylcholine (0.03–10μM) to the window dilated the arterioles, and topical application of epinephrine (0.03–3μM) constricted them dose-dependently without affecting the collecting venules and the venules. This method made possible the direct observation of the microvasculature in the basal mucosa of the stomach, in which common microvessel characteristics were shown.     

Apoptosis Induced by Ischemia–Reperfusion and Fasting in Gastric Mucosa Compared to Small Intestinal Mucosa in Rats

The effect of ischemia–reperfusion and 48-hr fasting on apoptosis was characterized in rat gastric mucosa and compared to small intestinal mucosa. Under halothane anesthesia, the celiac artery or superior mesenteric artery in the rat was occluded for 60 min followed by reperfusion. Occlusion of the celiac artery reduced blood flow in the stomach and occlusion of the mesenteric artery reduced blood flow in the small intestine. Additional rats were fasted for 48 hr to evaluate the effect of fasting on mucosal apoptosis. The ratios of fragmented DNA to total DNA, electrophoresis, and immunohistochemical staining were examined after ischemia–reperfusion or fasting. Apoptosis was not induced significantly in the gastric mucosa after ischemia–reperfusion, although it increased dramatically in the intestinal mucosa after ischemia–reperfusion. Further, after 48 fasting, apoptosis was induced in the small intestine, but not in the stomach. These results indicate that rat gastric mucosa is not as sensitive as small intestinal mucosa to ischemia–reperfusion or fasting-induced apoptosis.     

Pathophysiology of the gastric microcirculation.

Mucosal blood flow performs an extremely important role in microcirculation wherein alterations necessarily lead to severe gastric and duodenal mucosal lesions. The removal of back-diffused H+ ions through the adaptation of microcirculatory flow represents a valid defence mechanism. The blood flow's inability to contain H+ back-diffusion lies at the bottom of rapid-onset acute mucosal lesions; moreover, it probably contributes to the onset of chronic ulcer in certain areas already precariously supplied, because of the breakdown of the mucosal barrier or a further reduction in blood supply. Portal hypertension leads to altered blood flow in the gastric microcirculation. This haemo-dynamic condition brings about a series of endoscopically evident changes which are probably a consequence of the conspicuous increase in mucosal and submucosal vascular area. This haemodynamic situation may be an aetiopatho-genetic factor in the cirrhotic subject's marked sensitivity to gastric mucosal damage.     

Mechanisms of the inhibitory action of prostaglandins on meal-induced gastric secretion

In dogs with gastric fistula and Heidenhain pouch (HP), 15(S)-15-methyl prostaglandin E2 methyl ester (PG-S) infused intravenously in graded doses (0.5--2.0 microgram/kg/h) inhibited dose-dependently, meal-induced acid secretion both from the vagally innervated main stomach and from the HP. This inhibition was associated with a marked reduction in mucosal blood flow but without significant change in the ratio of aminopyrine concentration in the gastric juice and blood plasma, indicating that the reduction in gastric microcirculation was probably secondary to the inhibition of gastric secretion. In dogs with special cannulae that allowed complete separation of the stomach and the intestine, PG-S caused stronger inhibition of gastric acid and serum gastrin responses to gastric and intestinal meals after application directly to the gastric mucosa, than following duodenal administration. PG-S applied topically to the HP mucosa also suppressed direct chemical stimulation of the HP by L-histidine meal. We conclude that PG-S exerts its inhibitory action on gastric secretion both by local contact with the mucosa via suppression on gastrin release from the antral G-cells and by direct inhibition of the secretory activity of the oxyntic glands.     

Preparation of rat intestinal muscle and mucosa for quantitative microcirculatory studies.

This paper describes methods and procedural details for preparing either the rat intestinal muscle or mucosa for observation under the microscope. The tissues are transilluminated through a short optical clad rod with a standard condenser system. The tissue environment can be controlled, and the microcirculation of the muscle and mucosa are clearly visible and directly accessible. The arteries, veins, and nerves to the intestine can be simultaneously manipulated. One can therefore control a number of macro- and microcirculatory parameters, and perform a wide variety of quantitative measurements on either the intestinal muscle or mucosal vasculature.     

胃底腺黏膜型腺癌一例报道并文献复习

目的探讨胃底腺黏膜型腺癌的临床病理学特征及免疫组化表型。 方法总结山东省立医院西院病理科确诊的1例胃底腺黏膜型腺癌的临床及病理学资料,分析其组织形态学特点及免疫组织化学染色表达,并复习相关文献。 结果老年女性,胃底大弯侧见直径2.0 cm的不规则表浅隆起,中央浅糜烂,行内镜下黏膜剥脱术,肿瘤组织镜下为中-高分化管状腺癌,伴有乳头状腺癌,免疫组化染色小凹上皮分化区域MUC5AC(＋);胃底腺分化区域MUC6(＋)、pepsinogen-I(＋);Ki-67指数约5%。 结论胃底腺黏膜型腺癌是一种新的肿瘤类型,发病率极低,既有胃底腺型腺癌的内镜和病理特征,又有小凹上皮来源腺癌的内镜和病理特征;加强该肿瘤的认识有助于对其正确诊断与治疗。     

Effect of exogenous acid on the rat gastric mucosal microcirculation in hemorrhagic shock

In vivo microscopy and histology were used to study the effect of exogenous acid (0.1 N HCl) on the rat corpus mucosal microcirculation and bleeding in hemorrhagic shock. Systemic blood pressure was reduced stepwise by bleeding. Mucosal blood flow showed a significant linear correlation with mean systemic blood pressure. The flow stopped in half of the rats at 25% of control blood pressure, but red blood cells were always present within the microvessels. In contrast, the topical application of 0.1 N HCl accelerated the decrease of blood flow with graded hypotension and caused progressive disappearance of the honeycomblike network of red blood cell-filled superficial mucosal microvessels. After retransfusion, mucosal bleeding occurred in the area in which the blood-filled microvessels had disappeared. Histology revealed that the bleeding extended from the middle of the depth of the mucosa and was associated with tissue necrosis. These results indicate that exogenous acid in hemorrhagic shock causes increased mucosal ischemia and tissue damage with bleeding on retransfusion.