Failure of prostacyclin, beta-carotene, atropine and cimetidine to produce gastric cyto- and general mucosal protection in surgically vagotomized rats

Different chemicals (such as ethanol, HCl, drugs) produce gastric mucosal injury. A special type of gastric mucosal defense, which differed from the inhibition of gastric acid secretion, was discovered in response to small doses of prostaglandins. This phenomenon was termed "gastric cytoprotection". Later, the existence of gastric cytoprotection was proved using different compounds, such as vitamin A and other carotenoids, prostacyclin, small doses of anticholinergic and H2-blocking agents. These compounds produce cyto-protection by different mechanisms. In this study we tested the role of vagus nerve on the development of these different types of gastric cytoprotection. These compounds prevent ethanol-induced gastric mucosal injury in rats with intact vagus nerve, but their cyto- and mucosal protective effects disappear in surgically vagotomized rats. These results indicate that the intact vagus nerve is basically necessary for the overproduction of HCl and pepsin secretion, and for the development of gastric cytoprotection, produced by different compounds (e.g. prostacyclin, beta-carotene, small doses of atropine and cimetidine) acting without the presence of inhibition of gastric acid secretion.     

Correlation between the cytoprotective effect of beta-carotene and its gastric mucosal level in indomethacin (IND) treated rats with or without acute surgical vagotomy.

As to earlier observations that beta-carotene prevents the development of gastric mucosal injury produced by different noxious agent, however, its cytoprotective effect can be abolished by acute surgical vagotomy. The aim of this study was to evaluate the possible correlation between the gastric mucosal cytoprotective effect of beta-carotene and its gastric mucosal level in rats treated with IND. The gastric mucosal damage was produced by the administration of IND (20 mg/kg s.c.). The instillation of beta-carotene and acute surgical vagotomy (ASV) or SHAM operation were carried out 30 min before IND treatment. The rats were sacrificed 4 h after IND application, and the number and severity of gastric mucosal erosions were noted. The blood rats was collected quantitatively, the liver and the gastric mucosa were removed, and the beta-carotene and vitamin A level of the gastric mucosa, serum and liver were measured with HPLC. It was found that: 1. Beta-carotene induced gastric cytoprotection in SHAM-operated rats treated with IND but its effect disappeared after ASV. 2. Although the beta-carotene level of the gastric mucosa increased its concentration was not elevated in the serum of intact and vagotomized animals either. 3. Vitamin A Formation was not detected in the liver of animals with or without ASV. It was concluded that the lack of intake of beta-carotene into the gastric mucosa can not play etiologic role in the failure of gastric cytoprotection of rats with acute bilateral surgical vagotomy.     

Investigation of gastroprotective compounds at subcellular level in isolated gastric mucosal cells

We tested the hypothesis that recognized gastroprotective agents exert direct protection against ethanol-induced injury in isolated rat gastric mucosal cells in vitro. If protection exists, we also wanted to identify subcellular targets in the reversible and/or irreversible stages of cell injury. Ethanol-induced cell injury was quantified by measuring plasma membrane leakage (trypan blue exclusion and lactate dehydrogenase release), mitochondrial integrity (succinic dehydrogenase), and nuclear damage (ethidium bromide-DNA fluorescence). Initial cell viability and responsiveness were estimated by the effects of carbachol, carbachol + atropine, or 16,16-dimethyl-PGE(2) on chief cell pepsinogen secretion. Enriched parietal cells were stimulated by histamine, carbachol, or histamine + IBMX. Preincubation of cells with PG, sucrose octasulfate, or the sulfhydryl compounds N-acetylcysteine, taurine, or cysteamine increased cell resistance 相似文献   

Gastroduodenal ulceration following active immunization with prostaglandin E2 in dogs. Role of gastric acid secretion

In this study we present evidence to suggest that gastroduodenal mucosal defects may occur in gastric fistula dogs actively immunized with PGE2-thyroglobulin conjugate. One of four PGE2-immunized dogs developed a chronic pyloroduodenal ulcer with penetration into the pancreas and the other three had endoscopic evidence of gastric and/or duodenal erosions. In contrast, no gastroduodenal mucosal defects were seen in control dogs immunized with thyroglobulin alone. Occurrence of gastroduodenal ulcers or erosions was temporally related to formation of specific antibody to PGE2 suggesting that PGE2 antibody may be responsible for lesion formation. An increase in gastric acid secretion was not observed in PGE2-immunized dogs. Thus, it is likely that mucosal defects occur as a result of an impairment of PGE2-mediated mucosal defense mechanisms. Since gastroduodenal lesions can be visualized by endoscopy, the dog may prove to be useful in studying the role of endogenous PG in ulcer diseases.     

Mechanisms of action of retinoids in gastrointestinal mucosal protection in animals, human healthy subjects and patients.

Retinoids prevent chemically induced gastric mucosal damage without inhibiting gastric acid secretion ("nutritional gastric cytoprotection"). The gastroprotective effects of retinoids do not depend on 1) vitamin A activity; 2) number of unsaturated double bonds; 3) the presence of a characteristic chemical structure of their terminal components; however, they depend on 1) intact vagal nerve and 2) adrenals in experimental animals. The gastric cytoprotective effect of retinoids produces a dose-dependent inhibition of ATP-transformation into ADP. It also increases the transformation of ATP into cAMP. Other features of these gastric cytoprotective effects of retinoids include: 1) The retinoid-induced gastric mucosal protection differs from that of PGs; 2) The cAMP is an intracellular signal in the development of gastric mucosal damage produced by chemicals (e.g., ethanol, HCl, indomethacin) and in the protection of gastric mucosa induced by retinoids (but not by PGs); 3) The gastric mucosal protection induced by retinoids and gastric mucosal permeability can be separated in time. The existence of gastric mucosal protection can be demonstrated in healthy persons (against indomethacin treatment), in patients with gastric ulcer (GU) and duodenal ulcer (DU) without any inhibition of gastric acid secretion. The serum levels of vitamin A and zeaxanthin were significantly decreased in patients with chronic gastrointestinal (GI) inflammatory diseases (e.g., terminal ileitis, ulcerative colitis), colorectal polyposis, and different (e.g., esophageal, gastric, pancreatic, hepatocellular and colorectal) malignant diseases. The serum levels of vitamin A provitamins were unchanged and their GI mucosal protective effects do not depend on vitamin A activity. Conclusions: 1) Abundant experimental and human observations clearly proved the defensive role of retinoids in the GI tract; 2) There is a correlation between the a) scavenger properties of retinoids vs. intact vagal nerve; b) scavenging properties vs. intact adrenals. 3) The GI mucosal protective effect of retinoids is correlated with biochemical changes in the GI mucosa.     

Critical and timely review of the concept of gastric cytoprotection

Gastric cytoprotection is a concept or phenomenon, and not a single magic mechanism of action of unusual compounds. It refers to prevention of acute hemorrhagic erosions where the superficial epithelial cells are not directly protected but are rapidly replaced by restitution in microvascular injury in subepithelial capillaries is prevented or diminished and blood flow is maintained. This gastroprotection achieved by prostaglandins (PG), sulfhydryls (SH) and non-SH antioxidants is thus real but relative by target, mechanisms and in time. PG and SH are the only two chemical entities with both pharmacologic and biochemical relevance, i. e., endogenous concentrations of PG and SH derivatives may be measured biochemically and correlated with the degree of gastroprotection. Despite differences in the chemical mechanisms of action (e. g., SH unlike PG scavenge free radicals and may directly influence SH-sensitive receptors, enzymes and membrane permeability), the structural and functional targets for both groups of compounds are essentially the same: prevention or reduction of microvascular injury in subepithelial capillaries, maintenance of blood flow which allows the energy-requiring rapid epithelial restitution to repair the superficial epithelial defect. This reductionist, critical and mechanistic overview highlights the recent developments and the persisting problems in study design, definitions and interpretation of results as well as some critical questions related to the concept of gastric cytoprotection.     

Over-expression of 70-kDa heat shock protein confers protection against monochloramine-induced gastric mucosal cell injury

The major heat shock protein, HSP70, is known to be involved in cytoprotection against environmental stresses mediated by their function as a "molecular chaperone". Monochloramine (NH(2)Cl) is a potent cytotoxic oxidant generated by neutrophil-derived hypochlorous acid and Helicobacter pylori urease-induced ammonia. In this study, to evaluate the cytoprotective effect of HSP70 against NH(2)Cl-induced gastric mucosal cell injury, rat gastric mucosal cells (RGM-1) were stably transfected with pBK-CMV containing the human HSP70 gene (7018-RGM-1) or pBK-CMV alone (pBK-CMV-12) as control cells. These cells were treated with various concentrations of NH(2)Cl. Cell Viability was determined by MTT assay and the direct plasma membrane damage was analyzed by lactate dehydrogenase (LDH) release assay. Apoptosis was determined by DNA fragmentation analysis. NH(2)Cl caused injury to pBK-CMV-12 cells in a concentration-dependent manner. NH(2)Cl-induced gastric cell injury was significantly diminished in HSP70 over-expressing cell line (7018-RGM-1) both necrosis and apoptosis compared to the control cell line (pBK-CMV-12) transfected with CMV vector alone. These result suggest that overexpression of HSP70 plays an important role in protecting gastric cells against NH(2)Cl-induced injury.     

A pharmacological approach to cellular mechanisms of PGI2-induced gastric cytoprotection on ethanol-induced gastric mucosal damage in rats

The aims of this study were as follows: 1. to analyse the effects of drugs with different subcellular mechanisms on the PGI2-induced gastric cytoprotection in a non acid dependent (ethanol-induced) gastric ulcer model; 2. to identify the affinity and intrinsic activity curves on the PGI2-induced gastric cytoprotection; 3. to evaluate the main cellular mechanisms of PGI2-induced gastric mucosal defence. The observations were carried out on both sexes of CFY-strain rats, weighing 180 to 210 g. The gastric mucosal damage was produced by intragastric administration of 96% ethanol. The animals were killed at 1 hr after administration of ethanol, and the number and severity of gastric mucosal lesions (ulcers) was noted. Atropine, actinomycin D, cimetidine, mannomustine, dinitrophenol, epinephrine, pentagastrin, histamine, ouabain, tetracycline were given intraperitoneally (in different doses) at 30 min before administration of ethanol. The effects of these drugs were tested on the PGI2-induced (5 micrograms/kg was given intragastrically) gastric cytoprotection. It has been found that: 1. atropine, actinomycin D, cimetidine, epinephrine, ouabain, tetracycline and mannomustine inhibited the PGI2-induced gastric cytoprotection; 2. histamine, pentagastrin and 2,4-dinitrophenol enhanced the PGI2-induced gastric cytoprotection; 3. the molar concentrations of these drugs modifying the PGI2-induced gastric cytoprotection differed significantly. It has been concluded that: 1. the drugs stimulating or inhibiting the cell functions are capable to modify the extent of PGI2-induced gastric cytoprotection; 2. different subcellular mechanisms (oxidative phosphorylation, increased synthesis of proteins, ribonucleic and deoxyribonucleic acids, modifications of membrane-bound ATP-dependent energy systems) are involved in the development of PGI2-induced gastric cytoprotection.     

Detrimental effects of oestradiol on cysteamine-induced gastroduodenal ulceration in the female rat

The actions of the female sex steroid, oestradiol on cysteamine-induced mucosal ulceration has been evaluated in female Wistar rats. Administration of cysteamine (400 mg x kg(-1), s.c.) provoked macroscopic gastroduodenal mucosal injury (assessed planimetrically) and an increase in microvascular permeability (assessed by the extravasation of radiolabeled albumin) in the stomach and duodenum, determined 24 h later. Ovariectomy (2 weeks before cysteamine) reduced gastroduodenal macroscopic injury, and albumin extravasation following cysteamine challenge. Administration of oestradiol (1-5 mg x kg(-1), as an i.m. depot 1 week before cysteamine) dose-dependently augmented gastric and duodenal macroscopic mucosal lesions and microvascular permeability provoked by cysteamine. These findings indicate that oestradiol can exacerbate gastroduodenal ulceration and microvascular injury.     

Dual effect of female sex steroids on drug-induced gastroduodenal ulcers in the rat.

Since the sexual dimorphism of gastroduodenal ulcers is well known and might possibly relate to the actions of sex hormones, we studied the role of the female sex steroids, progesterone and 17beta-estradiol in cysteamine-induced mucosal ulcers in female Wistar rats (200-220 g). Administration of cysteamine (400 mg/kg, s.c.) provoked macroscopic gastroduodenal mucosa injury as assessed planimetrically, an increase in microvascular permeability in the stomach and the duodenum as assessed by extravasation of radiolabelled albumin, and decreased gastroduodenal mucus levels as assessed by the Alcian blue technique. Ovariectomy (2 weeks before cysteamine) decreased plasma 17beta-estradiol level as assessed by radioimmunoassay, gastroduodenal macroscopic injury and albumin extravasation, and increased mucus levels following cysteamine challenge. Administration of progesterone (10-50 mg/kg/week, s.c.) attenuated in a dose-dependent manner cysteamine-induced gastroduodenal mucosa injury and microvascular leakage, while it increased mucus levels in the stomach and the duodenum. In contrast, administration of 17beta-estradiol (1-5 mg/kg/week, s.c.) dose-dependently augmented gastric and duodenal macroscopic mucosa lesions and microvascular injury provoked by cysteamine, and caused a further reduction in gastroduodenal mucus levels observed after cysteamine administration. In different experiments, ovariectomy decreased indomethacin-induced gastroduodenal injury. The injection of 17beta-estradiol (1-5 mg/kg/week) did not affect gastroduodenal damage, while treatment with progesterone (10-50 mg/kg/week) protected against indomethacin-provoked mucosa ulcers. It is concluded that female sex steroids play a role in drug-induced gastroduodenal ulcers by modulating microvascular permeability and mucus secretion.     

Cholecystokinin secretagogue-induced gastroprotection: role of nitric oxide and blood flow

This study was done to examine the role of CCK in gastric mucosal defense and to assess the gastroprotective roles of nitric oxide and blood flow. In rats, the CCK secretagogues oleate and soybean trypsin inhibitor augmented gastric mucosal blood flow and prevented gastric injury from luminal irritants. Type A CCK receptor blockade negated CCK secretagogue-induced gastroprotection and exacerbated gastric injury from bile and ethanol but did not block adaptive cytoprotection. CCK secretagogue-induced gastroprotection and hyperemia were negated by nonselective nitric oxide synthase (NOS) inhibition (N(G)-nitro-L-arginine methyl ester) but not by selective inducible NOS inhibition (aminoguanidine). Gastric mucosal calcium-dependent NOS activity, but not calcium-independent NOS activity, was increased following CCK and CCK secretagogues. The release of endogenous CCK plays a role in the intrinsic gastric mucosal defense system against injury from luminal irritants. The protective mechanism appears to involve increased production of nitric oxide from primarily the constitutive isoforms of NOS and a resultant increase in blood flow.     

Role of endogenous prostacyclin in gastric ulcerogenic and healing responses--a study using IP-receptor knockout mice.

Endogenous prostaglandins (PGs) play an important role in the cytoprotective and healing responses in the stomach, by altering various functions, i.e., an increase of the mucosal blood flow, yet the role of prostacyclin (PGI(2)) and its receptor (IP-receptor) in these responses remains unclarified. In the present study, we used IP-receptor knockout mice [IP (-/-)] and examined the importance of IP-receptors in gastric ulcerogenic, cytoprotective and healing responses in these animals. The studies included the ulcerogenic response to cold-restraint stress, the cytoprotective response to a mild irritant (20 mM taurocholate: TC) and capsaicin, and the healing response of chronic gastric ulcers induced by thermo-cauterization. We first checked the absence of IP-receptors by examining the effect of cicaprost (a PGI(2) agonist, topical mucosal application) on gastric mucosal blood flow and found that this agent increased the mucosal blood flow in wild-type [WT (+/+)] mice but not in IP (+/-) mice. Cold-restraint stress (4 h) induced gastric lesions in both groups of mice, but the severity of damage was significantly greater in IP (-/-) mice. Prior p.o. administration of both TC and capsaicin exhibited a marked cytoprotection against HCl/ethanol-induced gastric damage in WT (+/+) mice, both responses being significantly mitigated in the presence of indomethacin. The adaptive cytoprotection induced by TC was similarly observed in IP (-/-) mice, while the capsaicin protection was totally attenuated in the animals lacking IP receptors. On the other hand, the healing of gastric ulcers was significantly delayed by daily administration of indomethacin in WT (+/+) mice. However, this process was not altered in IP (-/-) mice. These results suggest that endogenous PGI(2) is involved in the gastric ulcerogenic response to stress, but not in the healing of pre-existing gastric ulcers. In addition, PGI(2) and its receptors may play a crucial role in capsaicin-induced gastric protection but not in the adaptive cytoprotection-induced by mild irritants.     

Difference in chromatin sensitivity to heparin of chronic atrophic gastritis, of carcinoma-free and carcinoma-bearing stomach in comparison with normal gastric mucosa and gastric carcinoma as revealed by flow cytometry

DNA distribution patterns from gastric mucosal cells corresponding to four groups defined by histological examination were measured by flow cytometry before and after treatment with heparin, a polyanion. Group I comprised normal gastric mucosal cells; group II, chronic atrophic gastric mucosal cells originating from a carcinoma free stomach; group III, chronic atrophic gastric mucosal cells originating from a carcinoma bearing stomach; and group IV, malignant gastric mucosal cells. The heparin concentrations used were 1.25, 1.5, and 5 U/ml cell suspension. Heparin caused increases in fluorescence intensity and in coefficients of variation, which are interpreted as a reflection of alterations in chromatin structure. For the four groups investigated, the heparin-initiated changes were dependent, in varying degree, on concentration and time. Group I showed a much more extensive sensitivity to heparin than group IV. Group II and III reacted similarly to group I or group IV, depending on the source, i.e., either a carcinoma-free stomach or a carcinoma-bearing stomach. Further extension of this method might yield information concerning the real premalignant potential of a specific case of chronic atrophic gastritis.     

Gastric anti-ulcerogenic drug effect. A possible mechanism of its molecular basis.

During experimental gastric ulceration in rats an elevation in the mucosal cAMP/cGMP ratio can be encountered. The cause of this significant elevation is mainly (but not entirely) the dramatic fall of the cGMP level. Similar observations were obtained with prostacyclin application (100 micrograms/kg, p.o.), too. This prostaglandin derivative is well known, among others, because of its pronounced anti-ulcerogenic (cytoprotective) effect, too. Other substances of different molecular structure and properties may also exert such effect. The exact mechanism of action of this above-mentioned cytoprotection is still not completely understood. H2-receptor blocker drug cimetidine, given in such small dose (5 mg/kg, p.o.) which does not interfere with gastric acid secretion, also exerts very significant cytoprotective effect in stress (restraint)- and drug (indomethacin)-induced gastric ulcer models. Under cimetidine effect--together with a noticeable endogenous prostacyclin mobilization--the gastric mucosal cAMP/cGMP ratio was also strongly elevated. We conclude that this elevation in the mucosal cAMP/cGMP ratio might be a possible molecular basis of the gastric cytoprotective (anti-ulcerogenic) drugs but it needs further investigations whether all substances exerting cytoprotective effect, e.g. atropine, somatostatin, sulfhydryl drugs, etc., have the same "shifting" property or not? Moreover the phenomenon of the so-called "adaptive cytoprotection" can not be ruled out completely either, therefore this problem needs attention, too.     

Comparative mucosal microvasculature of the mammalian stomach

The comparative morphology of the gastric mucosal microvasculature was investigated using the corrosion casting technique. The vascular pattern consisted of a hexagonally arranged capillary plexus surrounding the gastric glands and terminating in venules running perpendicular to the mucosal axis. Vessels of the pyloric antrum demonstrated an acute angle between capillaries and venules, whereas vessels of the gastroduodenal junction changed from a honeycomb pattern to a leaf-like arrangement.     

Role of endogenous prostacyclin in gastric ulcerogenic and healing responses—a study using IP-receptor knockout mice

Endogenous prostaglandins (PGs) play an important role in the cytoprotective and healing responses in the stomach, by altering various functions, i.e., an increase of the mucosal blood flow, yet the role of prostacyclin (PGI₂) and its receptor (IP-receptor) in these responses remains unclarified. In the present study, we used IP-receptor knockout mice [IP (−/−)] and examined the importance of IP-receptors in gastric ulcerogenic, cytoprotective and healing responses in these animals. The studies included the ulcerogenic response to cold-restraint stress, the cytoprotective response to a mild irritant (20 mM taurocholate: TC) and capsaicin, and the healing response of chronic gastric ulcers induced by thermo-cauterization. We first checked the absence of IP-receptors by examining the effect of cicaprost (a PGI₂ agonist, topical mucosal application) on gastric mucosal blood flow and found that this agent increased the mucosal blood flow in wild-type [WT (+/+)] mice but not in IP (+/−) mice. Cold-restraint stress (4 h) induced gastric lesions in both groups of mice, but the severity of damage was significantly greater in IP (−/−) mice. Prior p.o. administration of both TC and capsaicin exhibited a marked cytoprotection against HCl/ethanol-induced gastric damage in WT (+/+) mice, both responses being significantly mitigated in the presence of indomethacin. The adaptive cytoprotection induced by TC was similarly observed in IP (−/−) mice, while the capsaicin protection was totally attenuated in the animals lacking IP receptors. On the other hand, the healing of gastric ulcers was significantly delayed by daily administration of indomethacin in WT (+/+) mice. However, this process was not altered in IP (−/−) mice. These results suggest that endogenous PGI₂ is involved in the gastric ulcerogenic response to stress, but not in the healing of pre-existing gastric ulcers. In addition, PGI₂ and its receptors may play a crucial role in capsaicin-induced gastric protection but not in the adaptive cytoprotection-induced by mild irritants.     

Endothelin induces vascular and mucosal lesions, enhances the injury by HCl/ethanol, and the antibody exerts gastroprotection.

Vascular factors play an important role in the pathogenesis and prevention of acute gastric mucosal lesions. Endothelin-3 (ET-3), a potent vasoactive peptide, was infused intra-arterially to induce gastric microvascular and hemorrhagic mucosal lesions, and to enhance the damaging effects of dilute HCl and ethanol. ET-3 antibody was injected intravenously to decrease hemorrhagic mucosal lesions induced by ethanol. Locally infused ET (0.01, 0.1, and 1.0 nmol.100 g-1.min-1 for up to 15 min) was followed in some cases by intragastric dilute ethanol or HCl, which alone caused no or only mild vascular and mucosal lesions. Monastral blue was used to visualize and quantify vascular injury. ET-3 produced dose-dependent vascular lesions that affected the walls of mucosal capillaries and venules and induced mucosal congestion and focal endothelial labeling in vessels of the gastric muscular layers. The highest dose of ET induced hemorrhagic gastric mucosal lesions, mortality, and periods of hyper- and hypotension in the rat. Medium and low doses of ET-3 caused vascular injury, and dose-dependently potentiated the vascular and hemorrhagic mucosal lesions caused by dilute HCl and ethanol. Indomethacin slightly enhanced damage induced by ET and 50% ethanol, suggesting a limited mediatory role of prostaglandins in the ET-induced mucosal lesions. Anti-ET-3 serum dose-dependently decreased but did not abolish the hemorrhagic gastric mucosal lesions induced by 75% ethanol. Thus, ET-3 causes endothelial damage in capillaries and venules of rat stomach and predisposes to mucosal damage even after exposure to dilute ethanol or HCl. ET is more potent than leukotrienes and histamine and thus may play an important role in the mechanisms of acute gastric mucosal injury and protection where the vascular network appears to be a major target.     

细胞更新对慢性饮酒大鼠胃黏膜适应性细胞保护的影响

目的: 以低浓度酒精作为弱刺激,通过慢性饮酒的大鼠动物模型,探讨慢性饮酒和大鼠胃粘膜适应性细胞保护作用之间的关系,以及胃粘膜细胞更新的作用.方法: 分别在饮酒不同时程的大鼠胃内灌注2 ml 100%酒精,分析胃粘膜的损伤情况.以流式细胞术、免疫组化和计算机图像处理技术观察大鼠胃粘膜的细胞增殖和凋亡,探讨胃粘膜的细胞更新情况.结果: ①纯酒精可使大鼠的胃体和胃窦出现溃疡和出血,饮用6%(v/v)酒精3～14 d的大鼠这种现象明显减轻,饮用6%(v/v)酒精1 d和28 d的大鼠则无改变.②饮用6%(v/v)酒精3～14 d的大鼠胃粘膜细胞更新加快,而饮酒28 d大鼠胃粘膜细胞凋亡增加,细胞增殖减少.结论: 细胞更新加快是适度低浓度酒精刺激引起的胃粘膜适应性细胞保护作用的重要原因,低浓度酒精刺激超过一定时限可引起胃粘膜萎缩性病变的趋势,使胃粘膜抵抗能力降低.     

Direct cellular effects of some mediators,hormones and growth factor-like agents on denervated (isolated) rat gastric mucosal cells

The brain-gut axis has an important role in the mechanism of gastric cytoprotection in vivo. The aim of this study was to evaluate the in vitro effect of protective agents without any central and peripheral innervation. A mixed population of rat gastric mucosal cells was isolated by the method of Nagy et al (Gastroenterology (1994) 77, 433–443). Cells were incubated for 60 min with cytoprotective drugs such as prostacyclin, histamine, pentagastrin and PL-10 substances (synthesized parts of BPC). At the end of this incubation cells were treated by 15% ethanol for 5 min. Cell viability was tested by trypan blue exclusion test and succinic dehydrogenase activity. The following results were obtained: 1) prostacyclin, histamine and pentagastrin had no direct cytoprotective effect on isolated cells; and 2) PL-10 substances significantly protected the cells against ethanol-induced cellular damage. This led to the following conclusions: 1) in the phenomenon of gastric cytoprotection only the growth factor-like agents have a direct cellular effect; and 2) the intact peripheral innervation is basically necessary for the development of mediators and hormone-induced gastric cytoprotection.     

The effect of etodolac on bile salt and histamine-mediated gastric mucosal injury in the rat

The effect of the selective cyclo-oxygenase-type-2 (COX-2) inhibitor etodolac on gastric mucosal integrity and gastric acid secretion was investigated in the rat. Etodolac was given in doses comparable with those being used in man for therapy of rheumatic conditions. The effect of etodolac was studied in the presence of a mild barrier breaker and in the presence of increased rates of endogenous acid secretion. In conscious pylorus-ligated rats, etodolac given intragastrically in 16 or 32 mg /kg for 3 h did not by itself give rise to visible gastric mucosal injury. Etodolac, however, exacerbated gastric mucosal injury evoked by intragastric application of acidified sodium taurocholate (5 mM in 150 mM HCl) in a dose-dependent manner. This effect of edotolac was independent of changes in gastric acid secretory responses. In rats whose gastric acid secretion was stimulated by intraperitoneal histamine (5 mg/kg), and etodolac (given i.g. in doses of 16 or 32 mg/kg) also increased gastric mucosal injury caused by histamine dose-dependently in the 3-h pylorus-ligated rats. Etodolac decreased gastric mucus in the saline- and in the sodium taurocholate-treated rats. In urethane-anaesthetized acute gastric fistula rats, intragastric etodolac (32 mg/kg) did not modify basal gastric acid secretion. Our data suggest that etodolac, a selective COX-2 inhibitor, impairs gastric mucosal resistance and can exacerbate gastric mucosal injury caused by other mucosal barrier breaking agents. Cyclooxygenase type-2 thus contributes to the gastric mucosal defences.