Modification by histamine H2-receptor blockade of acid secretion stimulated by histamine, pentagastrin and methacholine in the isolated whole mouse stomach.

The direct influences of the blockade of the gastric histamine H2-receptors on the secretory actions induced by histamine, pentagastrin and methacholine, have been studied on the isolated perfused whole mouse stomach. According to the results cimetidine did not modify the spontaneous basal acid secretion. The interactions of cimetidine with the secretagogues were of a competitive nature with histamine and non-competitive with pentagastrin, while no modification of methacholine stimulated acid secretion.     

Role of Na-K-2Cl cotransporter-1 in gastric secretion of nonacidic fluid and pepsinogen

Na-K-2Cl cotransporter-1 (NKCC) has been detected at exceptionally high levels in the gastric mucosa of several species, prompting speculation that it plays important roles in gastric secretion. To investigate this possibility, we 1) immunolocalized NKCC protein in the mouse gastric mucosa, 2) compared the volume and composition of gastric fluid from NKCC-deficient mice and their normal littermates, and 3) measured acid secretion and electrogenic ion transport by chambered mouse gastric mucosa. NKCC was localized to the basolateral margin of parietal cells, mucous neck cells, and antral base cells. In NKCC-deficient mice, gastric secretions of Na+, K+, Cl-, fluid, and pepsinogen were markedly impaired, whereas secretion of acid was normal. After stimulation with forskolin or 8-bromo-cAMP, chambered corpus mucosa vigorously secreted acid, and this was accompanied by an increase in transmucosal electrical current. Inhibition of NKCC with bumetanide reduced current to resting levels but had no effect on acid output. Although prominent pathways for basolateral Cl- uptake (NKCC) and apical Cl- exit [cystic fibrosis transmembrane conductance regulator (CFTR)] were found in antral base cells, no impairment in gastric secretion was detected in CFTR-deficient mice. Our results establish that NKCC contributes importantly to secretions of Na+, K+, Cl-, fluid, and pepsinogen by the gastric mucosa through a process that is electrogenic in character and independent of acid secretion. The probable source of the NKCC-dependent nonacidic electrogenic fluid secretion is the parietal cell. The observed dependence of pepsinogen secretion on NKCC supports the concept that a nonacidic secretory stream elaborated from parietal cells facilitates flushing of the proenzyme from the gastric gland lumen.     

Calcium, carbonic anhydrase and gastric acid secretion

Previous data concerning the action of calcium (Ca) on gastric acid secretion (GAS) indicated that calcium ions increase GAS elicited by gastrin released through a vagal mechanism, and also by a direct effect on parietal cells. Our research showed that the stimulating effect of calcium on gastric acid secretion can be antagonized by verapamil administration, which reduces gastric acid secretion . In the present study we followed the effect induced by administration of calcium and Ca-chelating agents (disodium EDTA) on gastric acid secretion and on carbonic anhydrase (CA) activity. We selected two groups of healthy volunteers: Group I (n=21) received a single i.v. dose of CaCl2 (15 mg/kg b.w.), whereas Group II (n=22) received a single i.v. dose of disodium EDTA (5 mg/kg b.w.). We determined blood calcium before and after treatment, gastric acid secretion at 2 hours. erythrocyte CA II activity, and CA IV activity in membrane parietal cells, which were isolated from gastric mucosa obtained by endoscopic biopsy. Assessment of carbonic anhydrase activity was achieved by the stopped-flow method. In Group I calcium administration increased blood calcium, HCl output, CA II and CA IV activity as compared to initial values. In Group II, disodium EDTA reduced blood calcium, HCl output, CA II and CA IV activity as compared to initial values. The results demonstrated that increased blood calcium and GAS values after calcium administration correlated with the increase of erythrocyte CA II and parietal cell CA IV activity, while disodium EDTA induced a reversed process. Our results also show that cytosolic CA II and membrane CA IV values are sensitive to calcium changes and they directly depend on these levels. Our data suggest that intra- and extracellular pH changes induced by carbonic anhydrase might account for the modulation of the physiological and pathological secretory processes in the organism.     

Effect of atrial peptide on gastric acid secretion in rats

The effect of synthetic rat atriopeptin (AP) II was examined on basal, vagally and carbachol-induced gastric acid secretion in anesthetized rats. AP II infusion, at stepwise increasing doses of 2, 20 and 100 ng/kg/min, had no effect on basal acid secretion. At doses of 2 and 20 ng/kg/min, AP II augmented vagally induced acid secretion significantly. The secretory response to vagal stimulation + AP II 20 ng/kg/min was completely abolished by atropine. In contrast a higher dose of AP II (50 ng/kg/h) reduced vagally induced acid secretion significantly. This dose of AP II also reduced acid secretion during direct cholinergic stimulation by carbachol, while the lower dose of 20 ng/kg/min had no effect on carbachol-induced acid secretion. The present data demonstrate for the first time an effect of atrial peptide on gastric acid secretion. At lower doses AP II augments the vagal influence on parietal cell function perhaps by augmenting vagally induced acetylcholine release. At higher doses AP II exerts an inhibitory effect on parietal cell function during vagally and carbachol-induced acid secretion, suggesting different and as yet unknown mechanisms of action. These results raise the possibility that the heart can exert a hormonally mediated influence on the regulation of gastric acid secretion.     

Effects of phenothiazines on acid secretion in the toad gastric mucosa

The effect of phenothiazine antipsychotic drugs on acid secretion was investigated in the isolated toad gastric mucosa. The acid secretory responses induced by maximal doses of histamine, carbachol and theophylline were all inhibited in a similar fashion by chlorpromazine. The ID50 was between 300 and 600 microM. Histamine-stimulated H+ secretion was also inhibited by trifluoperazine. Soluble cyclic AMP-dependent protein kinase activity was not significantly affected by 300 microM chlorpromazine. Microsomal (H+ + K+)-ATPase activity was significantly reduced by chlorpromazine. The results indicate that phenothiazines can inhibit acid secretion in the toad gastric mucosa and that inhibition of the gastric (H+ + K+)-ATPase may be involved in the mechanism of action.     

Effects of L-glutamic acid on acid secretion and mucosal blood flow in the rat stomach

The effect of intravenous administration of L-glutamic acid (L-Glu) on gastric acid secretion and gastric mucosal blood flow (GMBF) in anesthetized rats were investigated. Infusion with synthetic L-Glu alone had no effect on spontaneous acid secretion. However, L-Glu reduced histamine- (2 mg/kg/hr) or oxotremorine- (1 microg/kg/hr) stimulated acid secretion, whereas L-Glu had no effect on acid secretion induced by pentagastrin (8 microg/kg/hr). Furthermore, this inhibitory effect of L-Glu on histamine- or oxotremorine-stimulated acid secretion was blocked by 6,7-dinitroquinoxaline-2,3-dione (DNQX), a non-NMDA receptor antagonist. The effect of L-Glu on gastric mucosal microcirculation in the anesthetized rats was evaluated by using Laser Doppler Flowmetry (LDF). The results showed that L-Glu did not significantly reduce both mucosal and serosal blood flow in stomach. No significant modulatory effect on histamine- or oxotremorine-stimulated increase in GMBF was noted after infusion with L-Glu. It is concluded that L-glutamic acid is capable of the modulating of gastric acid secretion via ionotropic non-NMDA receptors, but do not affect on GMBF. However, L-glutamic acid showed no effect on acid secretion by itself.     

Modulation of gastric acid secretion by cannabinoids in rats

The current study aimed to evaluate the role of cannabinoid receptors in the regulation of gastric acid secretion and oxidative stress in gastric mucosa. To fulfill this aim, gastric acid secretion stimulated with histamine (5 mg/kg, subcutaneous [SC]), 2‐deoxy‐ d ‐glucose (D‐G) (200 mg/kg, intravenous) or ‐carbachol (4 μg/kg, SC) in the 4‐hour pylorus‐ligated rats. The CB1R agonist ( N‐arachidonoyl dopamine, 1 mg/kg, SC) inhibited gastric acid secretion stimulated by D‐G and carbachol but not in histamine, reduced pepsin content, and increased mucin secretion. Furthermore, it decreased malondialdehyde (MDA) and nitric oxide (NO) contents with an increase in glutathione (GSH) and paraoxonase 1 (PON‐1). Meanwhile, CB2R antagonist (AM630, 1 mg/kg, SC) inhibited gastric acid secretion stimulated by D‐G and reduced MDA and NO contents with an increase in GSH and PON‐1. Meanwhile, CB1R antagonist rimonabant or CB2R agonist GW 405833 had no effect on stimulated gastric acid secretion. Therefore, both CB1R agonist and CB2R antagonist may exert antisecretory and antioxidant potential in the stomach.     

Block of acid secretion by amytal and its partial reversal by menadione with ascorbate in the gastric mucosa of the guinea-pig

The effect of amytal on energy metabolism and acid secretion in an isolated gastric mucosa of the guinea-pig were studied. Determination of adenine nucleotides, creatine phosphate, pyruvate and lactate in the gastric mucosa showed that amytal depressed the levels of ATP, creatine phosphate and energy charge with elevation of the AMP and pyruvate levels. This treatment inhibited concomitantly acid secretion and active chloride transport detected by short circuit current. The addition of menadione with ascorbate to the medium in the presence of amytal partially restored ATP and energy charge levels and also induced a partial recovery of acid secretion and active chloride transport. These results suggest that ATP is a direct energy donor for acid secretion in the gastric mucosa of the guinea-pig.     

Pharmacological profile of a new peptidic gastrin antagonist

Boc-Trp-Met-Asp-NH2 was described as the smallest peptidic fragment which presented gastric antisecretory activity. Some pharmacological aspects of a peptide analogue, Boc-Trp-Leu-Asp-NH2 (Boc-WLD-NH2), were studied on the main biological functions of gastrin. This compound was found to inhibit the binding of gastrin to isolated gastric fundic mucosal cells (IC50 50 microM). On pentagastrin-induced gastric acid secretion in the rat, a dose-dependent inhibition was observed with an ID50 of 55 mumol/kg when pentagastrin (1 microgram/kg per h) was continuously infused and with an ID50 of 7.8 mumol/kg when pentagastrin (1 microgram/kg) was bolus i.v. injected. Similar inhibition was observed on acid secretion induced by pentagastrin in the isolated rat gastric mucosa (IC50 100 microM), whereas the tripeptide had no effect when acid output was triggered by histamine. A dose-dependent inhibition with the tripeptide was shown on pentagastrin induced guinea-pig ileum contractions (IC50 31 microM). The compound had no activity on histamine-stimulated guinea-pig atria (histamine H2-receptor). These results suggest some evidence for a selective antigastrin activity.     

Effects of the synthetic PGE1 derivative misoprostol on basal, stimulated and nocturnal acid secretion in duodenal ulcer cases. Mechanism of action

We studied the antisecretory effect of the synthetic PGE1 derivative misoprostol. Basal, histamine-stimulated and nocturnal acid secretion were determined on separate days in 3 groups of endoscopically confirmed duodenal ulcer patients. Misoprostol or placebo were given in random order in doses of 200, 400 and 800 mcg. H+ concentration, acid output and pH of gastric content were determined. Additionally, the effect of misoprostol on purified and gastric mucosa carbonic anhydrase was determined according to Maren's micromethod. Misoprostol reduced dose-dependently basal acid secretion (by 54% after 200 mcg, by 82% after 400 mcg and, respectively, by 94% after 800 mcg) as well as stimulated secretion which was reduced after the same doses by 22% (p less than 0.05), 48% and 64% (p less than 0.001), respectively. Nocturnal secretion was significantly reduced for a period of 4 h, with a consecutive rise of gastric pH. In vitro, misoprostol inhibited dose-dependently purified and gastric mucosa carbonic anhydrase basal activity. In conclusion, misoprostol inhibits basal, nocturnal and histamine-stimulated secretion in duodenal ulcer patients, an effect which could be mediated by inhibition of carbonic anhydrase.     

Effects of ethanol on gastric acid secretion and gastric mucosal cyclic AMP in the rat.

The effect of ethanol on the secretion of gastric acid and the content of cyclic AMP of the gastric mucosa was studied in rats. Intravenously, ethanol (10 to 800 mg/kg) had no effect on the output of acid. Upon local application into the stomach, ethanol (1 to 10%) caused a concentration-dependent inhibition of the output of gastric acid. The effect was evident within 5 min. At the concentration of 1 %,ethanol decreased the rate of acid secretion maximally by about 30%. At the concentration of 3 %, the maximal inhibition was about 70 %. At the concentration of 10 %, ethanol caused a total cessation of the output of acid within 20 to 60 min.Five and 25 min after the administration of 10 % ethanol into the stomach, the gastric mucosal content of cyclic AMP was decreased by approximately 50 %. Also in vitro, the mucosal content of cyclic AMP was decreased by ethanol within 5 min. The decrease was about 30 % with 2.5 % ethanol, approximately 60 % with 10 % ethanol, and approximately 45 % with 20 % ethanol. Alcohol inhibited the activity of the cyclic AMP phosphodiesterase of the gastric mucosa in a competitive manner. The K_i-value was 0.16 M which would correspond to an alcohol concentration of 9.1 % (v/v). Ethanol caused a concentration-dependent inhibition of the activity of the gastric mucosal adenyl cyclase. By 0.166 M (9.4 %) alcohol the inhibition was nearly 100 %.It is concluded that the ethanol-induced decrease of cyclic AMP in the gastric mucosa is due to a decreased formation of the nucleotide. The accompanying inhibition of the output of acid by ethanol is consistent with the view that cyclic AMP is an intracellular regulator of the gastric acid secretion. In view of the role of cyclic AMP in the control of the integrity of the cells, it is suggested that the ethanol-induced damage of gastric mucosa might also be, at least partly, due to the decreased mucosal content of cyclic AMP.     

Combined effects of neurotransmitters upon secretory function of the rat stomach at different functional states of the gastric mucosa

Peculiarities of the combined effects of acetylcholine (ACh) and serotonin (St) on the pattern of histamine (His)-induced gastric secretion were studied on intact rats and rats with gastric impairments. Destructive and hemorrhagic changes of the gastric mucosa were modeled by i.p. injections of noradrenaline. The gastric secretory function was estimated using a perfusion technique. It was shown that the above stressor influence resulted in impairment of 20–60% of the gastric mucosa surface. Combined action of ACh, St, and His in intact animals revealed a dominating effect of St on acid secretion. Acetylcholine and St modulated the secretory activity of main cells, but their combination exerted no clear effect on pepsinogen secretion. Serotonin, if used against the background of His injection, restrained acid and pepsin secretions. In the animals with structural and hemorrhage disturbances of the gastric mucosa, the secretion indices characterazing combined action of the neurotransmitters decreased.     

Effect of local injection with basic fibroblast growth factor (BFGF) and neutralizing antibody to BFGF on gastric ulcer healing, gastric secretion, angiogenesis and gastric blood flow.

Exogenous administration of bFGF was shown to accelerate tissue repair predominantly due to an increase in the formation of new microvessels (angiogenesis) suggesting that bFGF plays an important role in healing of gastric ulcer. This study was designed: 1) to examine the effect of local application of bFGF with or without neutralizing antibody (NA) to bFGF and 2) to determine the role of gastric secretion, gastric blood flow (GBF) at the ulcer margin and angiogenesis during gastric ulcer healing with or without local application of NA, bFGF or the combination of NA and bFGF. Chronic gastric ulcers were induced in Wistar rats by subserosal application of acetic acid (ulcer area 28 mm2) and gastric secretion during ulcer healing was assessed using animals additionally equipped with chronic gastric fistulas. The bFGF without or with NA to bFGF (10 ng/100 microl]), irrelevant antibodies (rabbit IgG; 10 microg/100 microl) or vehicle (saline) were locally injected into the subserosa immediately upon ulcer induction (day 0) and at day 2. Rats with acetic acid ulcers without subserosal injections served as controls. At day 11, all animals were anaesthetized and GBF was determined at the ulcer base, ulcer margin as well as in intact mucosa using the H2-gas clearance technique and the area of gastric ulcers was measured by planimetry. Gastric mucosa with ulcer was excised and the percentage of area covered with blood vessels, the number of fibroblasts and the percentage of connective tissue at the ulcer edge was assessed by histology. The gastric ulcers were healed spontaneously in control vehicle-treated rats at day 11 and this was accompanied by the significant increase in the GBF and number of microvessels in the ulcer area. The gastric secretion was suppressed immediately after ulcer induction and increased significantly at day 2 and day 11 but failed to return to that recorded in intact animals. In contrast, local application of bFGF inhibited gastric acid and pepsin outputs at each study time intervals tested and this effect was reversed by addition of NA to bFGF. Locally applied bFGF accelerated significantly ulcer healing and this was accompanied by the greater rise in the GBF of ulcer margin and more marked increase in number of microvessels as compared to those in vehicle-treated rats. Subserosal application of NA to bFGF prolonged significantly the ulcer healing and this effect was accompanied by a significant fall in the GBF at the ulcer margin and a decrease in number of capillaries in ulcer bed without significant alteration in gastric acid and pepsin outputs. The ulcer healing effect of bFGF and accompanying increase in the GBF at ulcer margin and in thenumber of microvessels as well as inhibition of gastric acid secretion evoked by bFGF were significantly attenuated by the addition of NA to bFGF. The number of fibroblasts and the distribution of connective tissue did not differ between groups studied. We conclude that; 1) depletion of endogenous bFGF at the ulcer area by specific NA to bFGF delays healing of gastric ulcers, reduces angiogenesis of ulcer bed and impairs the microcirculatory effect of this growth factor at the ulcer margin indicating that the availability of bFGF in the ulcer area plays a crucial role in the ulcer healing through induction of angiogenesis; 2) this prominent antiulcer effect of locally applied bFGF depends, at least in part, upon the inhibition of acid secretion by this peptide.     

MDL-646, a new synthetic E1-prostaglandin with local protective effects on the gastric mucosa

The gastric protection, diarrheogenic and arterial hypotensive effects of MDL-646, a PGE₁ derivative, have been studied in rats. The compound administered p.o. or i.v. was able to inhibit the maroscopic damage to gastric mucosa produced by noxious stimuli (ethanol and indomethacin). In the stomach perfusion test with the anesthetized rat, intravenously administered MDL-646 reduced histamine- or pentagastrin-stimulated gastric secretion. After intraduodenal administration (i.d.) doses at least 40–50 times greater were necessary for an antisecretory effect. In conscious rats with chronic gastric fistulas, intragastrically administered (i.g.) MDL-646 affected both acid concentration and volume of unstimulated gastric secretion. In experimental models for gastric lesions, DML-646 was much more potent after oral (p.o.) (15–30 times) than after i.v. administration. (ED₅₀ μg/kg: vs. alcohol lesions, 0.05 p.o. and 0.7 i.v.; vs. indomethacin ulcers, 7.0 p.o. and 195 i.v.). Our data would fit the hypothesis that it was a local effect on the gastric mucosa. The mechanism of this effect is not known. The supposed local activity coupled with the antisecretory effects and the good tolerability make it interesting to test MDL-646 as an anti-ulcer agent in man.     

The effect of ascorbic acid on Helicobacter pylori induced cyclooxygenase 2 expression and prostaglandin E2 production by gastric epithelial cells in vitro

BACKGROUND: Cyclooxygenase 2 (COX-2) is induced by the presence of Helicobacter pylori (H. pylori) on the gastric mucosa as part of the inflammatory response; this results in the synthesis of prostaglandins that amplify the local inflammatory response. The presence of H. pylori inhibits the secretion of ascorbate into the gastric lumen. Interestingly, ascorbate inhibits the growth of H. pylori and low dietary levels are associated with an increased risk of gastric adenocarcinoma. We therefore investigated the effect of ascorbate on H. pylori mediated COX-2 induction and prostaglandin production in vitro. METHODS: H. pylori was cocultured with gastric epithelial cells in the presence of ascorbate at physiological concentrations. The expression of COX-2 was assessed by Western blotting and prostaglandin E(2) (PGE(2)) was assessed by ELISA. RESULTS: Ascorbate inhibited gastric cell PGE(2) synthesis but not in COX-2 expression in response to H. pylori. In the absence of the organism, ascorbate also reduced PGE(2) expression in cells that constitutively express COX-2, again with no reduction of COX-2 protein expression. CONCLUSIONS: Physiological concentrations of ascorbate inhibit PGE(2) but not COX-2 expression in response to H. pylori in gastric epithelial cells.     

Capsaicin-sensitive afferent sensory nerves in modulating gastric mucosal defense against noxious agents.

In the rat stomach, evidence has been provided that capsaicin-sensitive sensory nerves (CSSN) are involved in a local defense mechanism against gastric ulcer. In the present study capsaicin or resiniferatoxin (RTX), a more potent capsaicin analogue, was used to elucidate the role of these sensory nerves in gastric mucosal protection, mucosal permeability, gastric acid secretion and gastrointestinal blood flow in the rat. In the rat stomach and jejunum, intravenous RTX or topical capsaicin or RTX effected a pronounced and long-lasting enhancement of the microcirculation at these sites, measured by laser Doppler flowmetry technique. Introduction of capsaicin into the rat stomach in very low concentrations of ng-microg x mL(-1) range protected the gastric mucosa against damage produced by topical acidified aspirin, indomethacin, ethanol or 0.6 N HCl. Resiniferatoxin exhibited acute gastroprotective effect similar to that of capsaicin and exerted marked protective action on the exogenous HCl, or the secretagogue-induced enhancement of the indomethacin injury. The ulcer preventive effect of both agents was not prevented by atropine or cimetidine treatment. Capsaicin given into the stomach in higher desensitizing concentrations of 6.5 mM markedly enhanced the susceptibility of the gastric mucosa and invariably aggravated gastric mucosal damage evoked by later noxious challenge. Such high desensitizing concentrations of capsaicin, however, did not reduce the cytoprotective effect of prostacyclin (PGI2) or beta-carotene. Capsaicin or RTX had an additive protective effect to that of atropine or cimetidine. In rats pretreated with cysteamine to deplete tissue somatostatin, capsaicin protected against the indomethacin-induced mucosal injury. Gastric acid secretion of the pylorus-ligated rats was inhibited with capsaicin or RTX given in low non-desensitizing concentrations, with the inhibition being most marked in the first hour following pylorus-ligation. Low intragastric concentrations of RTX reduced gastric hydrogen ion back-diffusion evoked by topical acidified salicylates. It is concluded that the gastropotective effect of capsaicin-type agents involves primarily an enhancement of the microcirculation effected through local release of mediator peptides from the sensory nerve terminals. A reduction in gastric acidity may contribute to some degree in the gastric protective action of capsaicin-type agents. The vasodilator and gastroprotective effects of capsaicin-type agents do not depend on vagal efferents or sympathetic neurons, involve prostanoids, histaminergic or cholinergic pathways.     

Study of the damaging effects of acetazolamide on gastric mucosa in rats

The present study demonstrated that acetazolamide (100 and 200 mg/kg, s.c.) induced severe gastric hemorrhagic ulceration in rats. The ulceration was aggravated by oral administration of HCl, but was inhibited by NaHCO3. Furthermore, the severity of ulceration was also decreased by pretreatment with methysergide, chlorpheniramine, or cimetidine. These protective effects were accompanied by an increase in serotonin and histamine released from the stomach. Acetazolamide injection also increased the protein level but reduced the sialic acid content in the gastric secretion, indicating that the gastric mucosal barrier may have been damaged. Prostaglandin E2 content of the gastric mucosa was not affected by the drug; however, carbonic anhydrase activity was markedly reduced in a dose-dependent manner. Thus, it is suggested that the ulceration induced by acetazolamide is mainly due to the inhibition of carbonic anhydrase activity and mucus secretion. The increase in serotonin and histamine release also may have been the contributing factors for gastric ulcer formation.     

Roles of endogenous prostaglandins and nitric oxide in gastroduodenal ulcerogenic responses induced in rats by hypothermic stress.

We examined the roles of endogenous prostaglandins (PGs) and nitric oxide (NO) in the gastroduodenal ulcerogenic responses to hypothermic stress (28 approximately 30 degrees C) in anesthetized rats. Lowering body temperature provoked damage in the gastroduodenal mucosa, with an increase of gastric acid secretion and motility. These responses were completely abolished by bilateral vagotomy or atropine, while 16,16-dimethyl PGE2 decreased the mucosal ulcerogenic response with no effect on acid secretion. The non-selective COX inhibitors, indomethacin or aspirin, worsened these lesions with enhancement of gastric motility and no effect on acid secretion, while the selective COX-2 inhibitor NS-398 did not affect any of these responses. On the other hand, the non-selective NOS inhibitor L-NAME but not aminoguanidine (a relatively selective inhibitor of iNOS), significantly potentiated the acid secretory and mucosal ulcerogenic responses in the stomach but reduced the duodenal damage in response to hypothermia, the effects being antagonized by co-administration of L-arginine. Hypothermia itself decreased duodenal HCO3- secretion under both basal and mucosal acidification-stimulated conditions. Both indomethacin and aspirin further decreased the HCO3- response to the mucosal acidification, while L-NAME significantly increased the HCO3- secretion even under hypothermic conditions, similar to 16,16-dimethyl PGE2. These results suggest that 1) hypothermic stress caused an increase of acid secretion and motility as well as a decrease of duodenal HCO3-secretion, resulting in damage in both the stomach and duodenum, 2) the COX-1 but not COX-2 inhibition worsened these lesions by enhancing gastric motility and further decreasing duodenal HCO3- response, 3) the cNOS but not iNOS inhibition worsened gastric lesions by increasing acid secretion but decreased duodenal damage by increasing HCO3- secretion. Thus, it is assumed that the gastroduodenal ulcerogenic and functional responses to hypothermic stress are modified by cNOS/NO as well as COX-1/PGs.     

巯基物质在消炎痛诱发大鼠胃粘膜损伤中的作用

本工作研究了巯基物质在消炎痛引起大鼠胃粘膜损伤中的可能作用。在胃粘膜损伤发生过程中、胃粘膜内非蛋白及蛋白结合的巯基物质含量均无明显降低。虽然半胱胺灌胃(132或264μmol)或皮下注射(132μmol)后均明显抑制消炎痛溃疡的发生,其抑制率分别为82％,92％和75％,但同样具有巯基的半胱氨酸却无保护作用。半胱胺(132μmol)皮下注射可使消炎痛大鼠胃酸分泌抑制46％,而灌胃则无此作用。两种途径给予的半胱胺均不影响胃壁结合粘液的分泌。这些结果表明,胃粘膜内巯基物质似不参与消炎痛的致溃疡过程。半胱胺在此种模型上虽有强烈的细胞保护作用,但似乎不是由于其分子上所带的巯基所致。因此,巯基物质在消炎痛引起的胃粘膜损伤模型上没有细胞保护作用。