胃(H~(+)+K~(+))-ATPase与急性胃粘膜病变的关系的研究

 本文对急性胃粘膜病变与胃粘膜(H~(+)+K~(+))-ATP_ase的关系作了初步探讨,实验结果说明以消炎痛为诱因引起大白鼠急性胃粘膜病变时胃粘膜上的胃酸分泌的质子泵(H~(+)+K~(+))-ATP_ase活力受到抑制。在离体实验中低浓度的消炎痛<2μmol,大白鼠胃粘膜(H~(+)+K~(+))-ATP_ase的活力便受到显著的抑制,在整体实验中维酶素对消炎痛引起的胃粘膜(H~(+)+K~(+))-ATP_ase的抑制具有保护作用。     

吗啡和纳洛酮对损毁下丘脑诱致的大鼠胃粘膜损伤之影响

本实验观察了静注吗啡和纳洛酮对电解损毁后部下丘脑诱致的大鼠胃粘膜损伤的影响并观察了在静注吗啡、纳洛酮后和侧脑室注射纳洛酮后其胃酸分泌和血清胃泌素水平之变化。实验揭示,吗啡仅略为降低该神经源性胃粘膜损伤程度,而纳洛酮则明显地减少其胃粘膜损伤;静注吗啡能抑制后部下丘脑损毁后大鼠的胃酸分泌,增加其血清胃泌素水平,而静注纳络酮后,这种大鼠的胃酸分泌增加,但血清胃泌素水平无明显变化;侧脑室注射纳洛酮对后部下丘脑损毁后大鼠胃酸分泌和血清胃泌素水平无明显影响。本结果表明,胃酸可能是导致这种消化道损伤的条件之一,而不是最重要因素;静注纳洛酮对后部下丘脑损毀后大鼠胃粘膜变化有保护作用。后者提示,内源性阿片样肽可能参与这种神经源性胃粘膜损伤的形成。     

cAMP在急性胃粘膜损害中的作用的研究

本研究应用ＲＩＡ法,观察了大鼠胃组织的ｃＡＭＰ含量与急性胃粘膜损害之间的关系。结果表明：（１）由消炎痛或失血性休克引起的急性胃粘膜损害时,胃组织ｃＡＭＰ含量明显降低;事先使用异搏定（１０ｍｇ／ｋｇ）可使胃组织ｃＡＭＰ含量明显增加,并使由消炎痛引起的急性胃粘膜损害相应减轻。（２）在正常情况下,胃窦、、胃体组织间ｃＡＭＰ含量并非相等,胃窦部组织ｃＡＭＰ含量高于胃体部组织,与此相应的是急性胃粘膜损害主要     

cAMP在急性胃粘膜损害中作用的研究

本研究应用ＲＩＡ法,观察了大鼠胃组织ｃＡＭＰ含量与急性胃粘膜损害之间的关系。结果表明：（１）由消炎痛或失血性休克引起的急性胃粘膜损害时,胃组织ｃＡＭＰ含量明显降低;事先使用异搏定（１０ｍｇ／ｋｇ）可使胃组织ｃＡＭＰ含量明显增加,并使由消炎痛引起的急性胃粘膜损害相应减轻。（２）在正常情况下,胃窦、胃体组织间ｃＡＭＰ含量并非相等,胃窦部组织ｃＡＭＰ含量高于胃体部组织,与此相应的是急性胃粘膜损害主要局限在胃体部。上述引起急性胃粘膜损害的诸因素均可使这种差别加大。５和１０ｍｇ／ｋｇ剂量的异搏定可使消炎痛所致急性胃粘膜损害的大鼠胃体部组织的ｃＡＭＰ含量明显增加,与胃窦部组织ｃＡＭＰ含量的差值变小,结果是胃体部粘膜的损害明显减轻。提示胃组织ｃＡＭＰ含量变化在急性胃粘膜损害中有一定的作用。     

胃(H~ K~ )-ATPase结构与功能的研究

胃(H~ K~ )-ATPase属于生物膜的第二类质子泵(E_1E_2型),从生理角度它是胃酸分泌的质子泵。本文结合我们初步的研究结果:猪、大白鼠胃粘膜(H~ K~ )-ATPase的纯化以及由消炎痛引起的急性胃粘膜病变与胃粘膜(H~ K~ )-ATPase的关系等,对此酶在近十几年来它的纯化、结构、性质、催化机理,向胃腔分泌盐酸的功能及其调节和胃病变的分子机理等方面进行了简要的综述。     

花生油对酒精所致胃粘膜损伤的保护作用

着重研究了花生油对无水酒精所引起的大白鼠胃粘膜损伤的保护作用,并对花生油作用的有效部位和机制作了初步探讨。     

损毁中缝大核对大鼠胃酸排出量及血清胃泌素水平的影响

本实验观察了损毁中缝大核对大鼠胃酸排出量和血清胃泌素水平的影响。实验表明:损毁中缝大核可增加胃酸排出量和血清胃泌素水平。切断双侧膈下迷走神经干可以消除这种作用,去除腹腔交感神经节及肠系膜上交感神经节只能部分减弱这种作用。     

消炎痛致胃粘膜损伤时胃组织胺含量变化及甲氰咪胍的影响

消炎痛可引起小鼠胃粘膜损伤,在一定剂量范围内,其剂量和胃粘膜损伤程度之间有明显的量效关系。在引起胃粘膜损伤时,胃组织胺含量相应增加,大剂量重度损伤时尤为明显。预先用甲氰咪胍灌胃,可明显减轻损伤并降低组织胺含量。提示组织胺参与消炎痛致胃粘膜损伤过程并对损伤产生一定影响。     

雌激素和孕激素对切除卵巢大鼠血清胃泌素水平和胃酸分泌的影响

卵巢切除两周后大鼠血清胃泌素水平升高和胃酸分泌增加;给予苯甲酸雌二醇(10μg/d)可完全阻止这两种变化,但补充黄体酮(0.2mg/d)对卵巢切除大鼠的血清胃泌素水平无影响,仅明显减少胃酸分泌。本实验结果提示,雌激素对于雌性大鼠的胃泌素释放和胃酸分泌具有抑制作用,孕激素也有抑制胃酸分泌的作用,这些作用不是摄食量改变的结果.     

胃(H++K+)-ATPase结构与功能的研究

胃(H⁺+K⁺)-ATPase属于生物膜的第二类质子泵(E₁E₂型),从生理角度它是胃酸分泌的质子泵。本文结合我们初步的研究结果:猪、大白鼠胃粘膜(H⁺+K⁺)-ATPase的纯化以及由消炎痛引起的急性胃粘膜病变与胃粘膜(H⁺+K⁺)-ATPase的关系等,对此酶在近十几年来它的纯化、结构、性质、催化机理,向胃腔分泌盐酸的功能及其调节和胃病变的分子机理等方面进行了简要的综述。     

Salicylic acid blocks indomethacin-induced cyclooxygenase inhibition and lesion formation in rat gastric mucosa

Salicylic acid has been shown to decrease gastric mucosal lesions induced by indomethacin in the rat. In vitro, it has also been shown to counteract the inhibitory effect of indomethacin and aspirin on the cyclooxygenase enzyme system in seminal vesicle microsomes and in platelets and vascular tissue. The hypothesis that the mechanism of salicylic acid "protection" against indomethacin-induced gastric lesions involves interference with indomethacin-induced mucosal cyclooxygenase inhibition was tested. Male, fasted rats were treated with intragastric salicylic acid in doses of 50, 100, 200, 300, or 400 mg/kg concomitantly with a sc injection of 20 mg/kg of indomethacin. Gastric mucosal lesions and mucosal cyclooxygenase activity (as measured by ex vivo prostaglandin F2 alpha synthesis) were examined 3 hr later. Intragastric salicylic acid, 200-400 mg/kg, significantly reduced indomethacin-induced lesion formation, while counteracting significantly indomethacin inhibition of prostaglandin synthesis. Salicylic acid alone did not significantly change cyclooxygenase activity. It is concluded that topical salicylic acid can decrease indomethacin-induced gastric mucosal lesion in the rat, in part, by counteracting the inhibitory effect of indomethacin at the cyclooxygenase level.     

Centrally administered NPY stimulated gastric acid and pepsin secretion by a vagally mediated mechanism

We investigated the possible roles of centrally administered neuropeptide Y (NPY) on gastric secretion, serum gastrin levels and gastric mucosal blood flow in anesthetized rats. Centrally administered NPY dose-dependently stimulated gastric acid and pepsin secretion. The stimulatory effect of intracerebroventricular administration of NPY was more potent than that of intracisternal administration. Centrally administered NPY also increased gastric secretion in the central noradrenaline depleted rats. In contrast, intravenously administered NPY had no influence on gastric secretion. These stimulatory effects were abolished by vagotomy or atropine pretreatment. The serum gastrin levels did not change after central NPY injection. Although intravenously administered NPY slightly increased gastric mucosal blood flow, centrally administered NPY slightly diminished gastric mucosal blood flow. These results indicate that centrally administered NPY markedly influences gastric functions in the rat.     

The role of food intake on gastric mucosal growth and gastrin receptors during pregnancy and lactation

We examined the effects of pregnancy and lactation on mucosal growth and the numbers and affinity of gastrin receptors in the oxyntic gland mucosa in rats and compared these with changes in serum gastrin levels and food consumption. Gastric mucosal DNA, RNA, and protein contents were significantly increased during lactation. These changes were not observed in either pregnant or nonlactating rats which had given birth at the same time as the lactating animals. The gastrin-binding capacity of a membrane fraction of the oxyntic mucosa was also increased at the corresponding periods in lactating rats (Days 7, 15, 20). Scatchard plot analysis revealed that the number of gastrin receptors was significantly increased without any change in affinity. Food consumption and levels of serum gastrin remained unaltered in pregnant and non-lactating rats compared to virgin controls, but were significantly increased in lactating rats. Increased serum gastrin levels and gastrin binding capacities in lactating rats (Day 15) were abolished by preventing increased food consumption by means of pair feeding. The results demonstrate that the number of gastrin receptors in the oxyntic mucosa increases during lactation in rats. This increase is probably due to hypergastrinemia caused by increased food intake. The increased number of gastrin receptors may be involved in the mechanism of hypertrophic responses of the gastric mucosa in lactating rats.     

Gastric prostacyclin (PGI2) prevents stress-induced gastric mucosal injury in rats primarily by inhibiting leukocyte activation.

We investigated whether, in rats, gastric prostacyclin (PGI2) prevented gastric mucosal injury that was induced by water-immersion restraint stress by inhibiting leukocyte activation. Gastric levels of 6-keto-PGF1alpha, a stable metabolite of PGI2, increased transiently 30 min after stress, followed by a decrease to below the baseline 6-8 h after stress. Gastric mucosal blood flow decreased to approximately 40% of the baseline level 8 h after stress. Myeloperoxidase activity was significantly increased 8 h after stress. Treatment with indomethacin before stress inhibited the increase in 6-keto-PGF1alpha levels and markedly reduced mucosal blood flow. It also markedly increased leukocyte accumulation and mucosal lesion formation. Iloprost, a stable PGI2 analog, inhibited the indomethacin-induced decrease in mucosal blood flow, mucosal lesion exacerbation, and increase in leukocyte accumulation. Nitrogen mustard-induced leukocytopenia inhibited the indomethacin-associated lesion exacerbation and the increase in leukocyte accumulation, but not the decreases in mucosal blood flow. These observations indicate that gastric PGI2 decreases gastric mucosal lesion formation primarily by inhibiting leukocyte accumulation.     

The protective action of melatonin on indomethacin-induced gastric and testicular oxidative stress in rats

Reactive oxygen species and lipid peroxidation play a role in the pathogenesis induced by the non-steroidal anti-inflammatory drug indomethacin. Melatonin (MLT) protection against indomethacin-induced oxidative tissue injury was investigated in gastric mucosa and testis of rats. MLT was administered intragastrically (i.g.) 30 min before the administration to fasted rats of 20 mg indomethacin/kg rat given i.g.. The area of gastric lesion as well as thiobarbituric acid reactive substances (TBARS) and lactate dehydrogenase (LDH) activity were found to be significantly increased 4 h after administration of indomethacin in rat gastric mucosa and testis indicating acute oxidative injury. MLT pretreatment reduced gastric lesion area to 80% of the indomethacin-treated rats and reduced the rise in TBARS concentration. MLT treatment reduced the LDH activity increase in testis but not in gastric mucosa. In indomethacin-treated rats, both the cytosolic Cu,Zn superoxide dismutase (Cu,Zn-SOD) and mitochondrial Mn-SOD activities were significantly diminished in gastric mucosa as well as the total SOD activity in testis. In addition, glutathione (GSH) content in both tissues was markedly decreased following indomethacin treatment. Pretreatment with MLT significantly ameliorated both the inhibition of SOD activity and the decreased GSH content in both tissues. Thus, these results show the effective antiperoxidative and preventive actions of MLT against indomethacin-induced gastric mucosal damage and testicular oxidative injury and we propose that this action might be relevant for its use with other free radical generating drugs.     

Effect of sialoadenectomy on stomach lesions induced by indomethacin and ethanol in relation to gastric vascular permeability, the gastrin level and HCl secretion in rats.

Stomach lesions induced by indomethacin (20 mg.kg-1 i.p.) and ethanol (1 ml 95% intragastrically) were studied after a 24 hour fast in rats which had undergone sialoadenectomy. The size of the lesions was correlated with gastric HCl secretion, with gastric vascular permeability (determined from the Evans blue concentration in the stomach tissue after its i.v. administration) and with the serum gastrin level. These parameters were also studied in sialoadenectomized rats and in animals given epidermal growth factor (EGF) (50 lg.kg-1). It was found that sialoadenectomy significantly (p < 0.01) raised the incidence of stomach lesions after the administration of indomethacin and also after ethanol (p < 0.05). A significant increase in both basal and stimulated HCl secretion was found after sialoadenectomy. Both indomethacin and ethanol also increased gastric vascular permeability in rats not subjected to sialoadenectomy, but sialoadenectomy raised it significantly compared with the non-sialoadenectomized group. The serum gastrin levels fell after sialoadenectomy and the decrease was significant after the subsequent administration of indomethacin or ethanol. The administration of EGF to sialoadenectomized rats lowered the incidence of stomach lesions, inhibited HCl secretion and reduced vascular permeability. The lowered susceptibility of the gastric mucosa to the formation of lesions in sialoadenectomized rats given indomethacin or ethanol can be regarded as the outcome of the uptake of EGF.     

Lack of histamine alters gastric mucosal morphology: comparison of histidine decarboxylase-deficient and mast cell-deficient mice

Histamine plays an important role in the regulation of gastric acid secretion; however, its role in maintenance of gastric morphology remains unclear. To clarify the necessity of histamine for gastric mucosal development and maintenance, we evaluated two different kinds of mice that lacked either mast cells (one of the gastric histamine-producing cell types) or histidine decarboxylase (HDC; a histamine-synthesizing enzyme). Measurements of stomach weight, intragastric pH, mucosal histamine levels, as well as serum gastrin and albumin levels were performed in mice. Gastric mucosal appearance was examined by immunohistochemical techniques. Although gastric mucosal histamine levels in mast cell-deficient mice were half of those observed in the wild-type mice, intragastric pH, serum gastrin levels, and gastric morphology at 12 mo were unchanged compared with the wild-type mice. In contrast, HDC-deficient mice possessed no detectable gastric histamine, but did exhibit hypergastrinemia, as well as marked increases in intragastric pH and stomach weight compared with the wild-type mice. Histological analysis revealed that 9-mo-old HDC-deficient mice demonstrated hyperplasia in the oxyntic glandular base region, as well as increased numbers of parietal and enterochromaffin-like cells. These results indicate that enterochromaffin-like cell-derived histamine is potentially involved in gastric mucosal morphology regulation.     

Cannabinoid HU210 Protects Isolated Rat Stomach against Impairment Caused by Serum of Rats with Experimental Acute Pancreatitis

Acute pancreatitis (AP), especially severe acute pancreatitis often causes extra-pancreatic complications, such as acute gastrointestinal mucosal lesion (AGML) which is accompanied by a considerably high mortality, yet the pathogenesis of AP-induced AGML is still not fully understood. In this report, we investigated the alterations of serum components and gastric endocrine and exocrine functions in rats with experimental acute pancreatitis, and studied the possible contributions of these alterations in the pathogenesis of AGML. In addition, we explored the intervention effects of cannabinoid receptor agonist HU210 and antagonist AM251 on isolated and serum-perfused rat stomach. Our results showed that the AGML occurred after 5 h of AP replication, and the body homeostasis was disturbed in AP rat, with increased levels of pancreatic enzymes, lipopolysaccharide (LPS), proinflammtory cytokines and chemokines in the blood, and an imbalance of the gastric secretion function. Perfusing the isolated rat stomach with the AP rat serum caused morphological changes in the stomach, accompanied with a significant increment of pepsin and [H⁺] release, and increased gastrin and decreased somatostatin secretion. HU210 reversed the AP-serum-induced rat pathological alterations, including the reversal of transformation of the gastric morphology to certain degree. The results from this study prove that the inflammatory responses and the imbalance of the gastric secretion during the development of AP are responsible for the pathogenesis of AGML, and suggest the therapeutic potential of HU210 for AGML associated with acute pancreatitis.