cyclic-gmp and Stomach-Ulcer

The intracellular effect of exogenously administered prostacyclin in the gastric mucosa seems to be a polyphasic effect, namely: 1. Effect on the cyclic nucleotide (cAMP, cGMP), turnover; 2. Effect on the calmodulin-content; 3. DNA and RNA changes; 4. Influence on protein synthesis; 5. New cell formation. While the endogenous prostacyclin exerts a natural protection against damaging noxae.

Topics: Animals; Calcium; Calmodulin; Cyclic AMP; Cyclic GMP; Epoprostenol; Gastric Mucosa; Humans; Smoking; Stomach Ulcer

Peptic ulcers are one of the world's major gastrointestinal disorders, embracing both gastric and duodenal ulcers, and affecting 10% of the world population. The current study aimed to investigate the possible protective effect of tadalafil and pentoxifylline (PTX) on indomethacin-induced peptic ulcers. Male albino rats were divided into five groups: control group; ulcerated group; Indomethacin + Tadalafil, in which animals were pretreated with tadalafil orally before indomethacin; Indomethacin+ PTX, in which animals were pretreated with PTX orally before indomethacin; and Indomethacin + Tadafil + PTX. Indomethacin treatment revealed histopathological changes and ulcer scoring and ulcer index were markedly increased. Serum levels of prostaglandin and heme oxygenase-1 were significantly decreased. The ulcerogenic also induced marked oxidative stress as evident from the increased malondialdehyde, decreased in gastric glutathione content and superoxide dismutase activity, while the gastric myeloperoxidase was increased. Gastric nitric oxide content was decreased and the expression of vascular endothelial growth factor was downregulated while the tumor necrosis factor α (TNF-α) level was dramatically increased. Pretreatment of the ulcerative group by either tadalafil or PTX or their combination improved all these pathological changes. Tadalafil or PTX may have a role in protecting gastric mucosa damage caused by indomethacin which may be useful in the future for the treatment of gastric ulceration.

Topics: Animals; Cyclic GMP; Dinoprostone; Indomethacin; Male; Malondialdehyde; Nitric Oxide; Pentoxifylline; Rats; Stomach Ulcer; Tadalafil; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor A

Chronic use of alendronate has been linked to gastrointestinal tract problems. Our objective was to evaluate the role of the NO/cGMP/KATP signaling pathway and nitric oxide synthase expression in alendronate-induced gastric damage. Rats were either treated with the NO donor, sodium nitroprusside (SNP; 1, 3, and 10 mg/kg), or the NO synthase (NOS) substrate, L-arginine (L-Arg; 50, 100, and 200 mg/kg). Some rats were pretreated with either ODQ (a guanylate cyclase inhibitor; 10 mg/kg) or glibenclamide (KATP channels blocker; 10 mg/kg). In other experiments, rats were pretreated with L-NAME (non-selective NOS inhibitor; 10 mg/kg), 1400 W (selective inducible NOS [iNOS] inhibitor; 10 mg/kg), or L-NIO (a selective endothelial NOS [eNOS] inhibitor; 30 mg/kg). After 1 h, the rats were treated with alendronate (30 mg/kg) by gavage for 4 days. SNP and L-Arg prevented alendronate-induced gastric damage in a dose-dependent manner. Alendronate reduced nitrite/nitrate levels, an effect that was reversed with SNP or L-Arg treatment. Pretreatment with ODQ or glibenclamide reversed the protective effects of SNP and L-Arg. L-NAME, 1400 W, or L-NIO aggravated the severity of alendronate-induced lesions. In addition, alendronate reduced the expression of iNOS and eNOS in the gastric mucosa. Gastric ulcerogenic responses induced by alendronate were mediated by a decrease in NO derived from both eNOS and iNOS. In addition, our findings support the hypothesis that activation of the NO/cGMP/KATP pathway is of primary importance for protection against alendronate-induced gastric damage.

Topics: Administration, Oral; Alendronate; Animals; Cyclic GMP; Dose-Response Relationship, Drug; Female; KATP Channels; Nitric Oxide; Nitric Oxide Synthase; Rats; Rats, Wistar; Signal Transduction; Stomach Ulcer; Structure-Activity Relationship

Based on ethnopharmacological indications that Mentha species may be used in the treatment of gastrointestinal diseases, this study aimed to characterize the gastroprotective mechanisms of menthol (ME), the major compound of the essential oil from species of the genus Mentha. The gastroprotective action of ME was analyzed in gastric ulcers that were induced by ethanol or indomethacin in Wistar male rats. The mechanisms responsible for the gastroprotective effect were assessed by analyzing the amount of mucus secreted, involvement of non-protein sulfhydryl (NP-SH) compounds, involvement of calcium ion channels and NO/cGMP/K(+)ATP pathway, gastric antisecretory activity and the prostaglandin E2 (PGE2) production. The anti-diarrheal activity and acute toxicity of ME were also evaluated. Oral treatment with ME (50mg/kg) offered 88.62% and 72.62% of gastroprotection against ethanol and indomethacin, respectively. There was an increased amount of mucus and PGE2 production. The gastroprotective activity of ME involved NP-SH compounds and the stimulation of K(+)ATP channels, but not the activation of calcium ion channels or the production of NO. The oral administration of ME induced an antisecretory effect as it decreased the H(+) concentration in gastric juice. ME displayed anti-diarrheal and antiperistaltic activity. There were no signs of toxicity in the biochemical analyses performed in the rats' serum. These results demonstrated that ME provides gastroprotective and anti-diarrheal activities with no toxicity in rats.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Calcium Channels; Castor Oil; Cyclic GMP; Diarrhea; Dinoprostone; Ethanol; Indomethacin; Male; Menthol; Nitric Oxide; Potassium Channels; Rats; Rats, Wistar; Signal Transduction; Stomach Ulcer; Sulfhydryl Compounds

Carbenoxolone, a semi-synthetic triterpenoid, exhibits gastroprotective activity related to the participation of nitric oxide (NO); however, the complete NO/(c) GMP/K(ATP) channels pathway for carbenoxolone is unknown. Therefore the aim of this study was to examine the NO/(c) GMP/K(ATP) channels pathway as the gastroprotective mechanism of carbenoxolone in the ethanol-induced gastric injury model in the rat. Oral administration of carbenoxolone (30 mg/kg, p.o.) exhibited gastroprotective effect against ethanol-induced gastric injury in rats. Pretreatment with N(G) -nitro-l-arginine methyl ester (L-NAME, 70 mg/kg, i.p.); 1H-[1,2,4]oxadiazolo[4,3-a]quinoxaline-1-one (ODQ, guanylate cyclase inhibitor, 10 mg/kg, i.p.); or glibenclamide (K(ATP) channels inhibitor, 1 mg/kg, i.p.) reversed the gastroprotective effect of carbenoxolone for ethanol-induced gastric injury. Furthermore, gastric prostaglandins and NO levels increased after carbenoxolone administration in ethanol-induced gastric injury in rats. In conclusion, our results suggest that the increase of NO levels in gastric tissue after pretreatment with carbenoxolone activates the NO/(c)GMP/K(ATP) channels pathway, the principal gastroprotective mechanism of carbenoxolone.

Topics: Administration, Oral; Animals; Anti-Ulcer Agents; Carbenoxolone; Cyclic GMP; Ethanol; KATP Channels; Male; Nitric Oxide; Prostaglandins; Rats; Rats, Wistar; Stomach Ulcer

Sildenafil is a selective inhibitor of cGMP-specific phosphodiesterase. Sildenafil, acting via NO-dependent mechanisms, prevents indomethacin-induced gastropathy. Activation of ATP-sensitive potassium channels (K(ATP)) is involved in gastric defence. Our objective was to evaluate the role of the NO/cGMP/K(ATP) pathway in the protective effects of sildenafil against ethanol-induced gastric damage.. Rats were treated with L-NAME (1 or 3 mg kg(-1), i.p.) or with L-arginine (200 mg kg(-1), i.p.) + L-NAME (3 mg kg(-1), i.p.), the guanylate cyclase inhibitor, ODQ (10 mg kg(-1), i.p.), glibenclamide (0.1, 0.3, 1 or 3 mg kg(-1), i.p.) or with glibenclamide (1 mg kg(-1), i.p.) + diazoxide (3 mg kg(-1), i.p.). After thirty minutes, the rats received sildenafil (1 mg kg(-1), by gavage), followed by intragastric instillation of absolute ethanol (4 ml kg(-1)) to induce gastric damage. One hour later, gastric damage (haemorrhagic or ulcerative lesions) was measured with a planimetry programme. Samples of stomach were also taken for histopathological assessment and for assays of tissue glutathione and haemoglobin.. Sildenafil significantly reduced ethanol-induced gastric damage in rats. L-NAME alone, without L-arginine, significantly reversed the protection afforded by sildenafil. Inhibition of guanylate cyclase by ODQ completely abolished the gastric protective effect of sildenafil against ethanol-induced gastric damage. Glibenclamide alone reversed sildenafil's gastric protective effect. However, glibenclamide plus diazoxide did not alter the effects of sildenafil.. Sildenafil had a protective effect against ethanol-induced gastric damage through the activation of the NO/cGMP/K(ATP) pathway.

Topics: Animals; Arginine; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Diazoxide; Disease Models, Animal; Enzyme Inhibitors; Ethanol; Gastric Mucosa; Glutathione; Glyburide; Guanylate Cyclase; Hemoglobins; KATP Channels; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Oxadiazoles; Peptic Ulcer Hemorrhage; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Piperazines; Potassium Channel Blockers; Purines; Quinoxalines; Rats; Rats, Wistar; Signal Transduction; Sildenafil Citrate; Stomach Ulcer; Sulfones

Although sildenafil (Viagra) and other phosphodiesterase V (PDE V) inhibitors are increasingly recognized for their use in the treatment of male erectile dysfunction and perhaps more recently pulmonary artery hypertension, less is known of their potential beneficial effects in other situations. Medeiros et al., in the current issue of the British Journal of Pharmacology, report that sildenafil dramatically reduces alcohol-induced gastric damage in rats. The authors provide convincing evidence that such protection not only occurs via the nitric oxide (NO)/cGMP pathway, but also involves regulation of ATP-sensitive potassium channels. Therefore, in addition to exerting anti-impotence efficacy, PDE V inhibitors may provide significant beneficial effects from mucosal injury induced by alcohol.

Topics: Animals; Arginine; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Disease Models, Animal; Ethanol; Gastric Mucosa; Glutathione; Guanylate Cyclase; Hemoglobins; KATP Channels; Nitric Oxide; Nitric Oxide Synthase; Peptic Ulcer Hemorrhage; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Piperazines; Purines; Rats; Signal Transduction; Sildenafil Citrate; Stomach Ulcer; Sulfones

In addition to the depletion of prostaglandins (PGs), oxygen free radicals generation and nitrogen species haven been implicated in non-steroidal anti-inflammatory drugs (NSAIDs)-induced gastric injury. The aim of the present study was to examine changes in PGE2 generation and its relationship with proinflammatory parameters and nitric oxide (NO) production in the comparative pathogenesis of gastric injury induced by metamizol vs. diclofenac, NSAIDs that present different gastric tolerability and cyclooxygenase (COX) inhibition profiles.. Studies were performed in Wistar-Han rats.. Metamizol (120, 500 and 1,000 mg/kg body weight) and diclofenac (50 mg/kg body weight) were given by oral administration.. Determinations were made of macroscopic and histological evaluation of gastric mucosal injury, gastric prostaglandin synthesis (PGE2 levels), myeloperoxidase activity (MPO), tumor necrosis factor-alpha levels (TNF-a), cyclic guanosine monophosphate (cGMP), nitric oxide synthase activity (NOS) and NOS mRNA expression.. Metamizol, only at the highest doses assayed, provoked weak lesions in the gastric mucosa. To the contrary, diclofenac treatment presented the highest grade of lesion. All treatments decreased PGE2 gastric generation. Treatment of the animals with metamizol neither modified the MPO activity nor TNF-alpha levels. In contrast, statistically significant increases in both parameters were observed after diclofenac administration. cGMP levels were not influenced with diclofenac treatment, nevertheless metamizol reduced the nucleotide levels, which was accompanied by an inhibition of constitutive NOS (cNOS) activity without modifying the mRNA expression of the enzyme.. In addition to inhibition of PG synthesis, damage induced by metamizol was associated with an inhibition of the NO/cGMP pathway and cNOS activity. In contrast, diclofenac-induced gastric damage was associated with an increase of the inflammatory response.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Cyclic GMP; Diclofenac; Dipyrone; Dose-Response Relationship, Drug; Female; Gastric Mucosa; Male; Nitric Oxide; Nitric Oxide Synthase; Peroxidase; Prostaglandins; Rats; Rats, Wistar; Stomach Ulcer; Tumor Necrosis Factor-alpha

Previous studies have shown that excitatory amino acids (EAAs) and their receptors may play important roles in the mammalian enteric system. In this study, we investigated whether EEAs, including L-glutamate (L-Glu) and subtypes N-methyl-D-aspartate (NMDA), kainic acid (KA), and quisqualic acid (QA), reduce cyclic AMP (cAMP) levels and play a role in protecting gastric lesions in cold-restraint stress (CRS) mice. First, we found that dose-dependent administration of four selected EAAs significantly attenuated the increase of cAMP content and exhibited a protective effect on the development of gastric lesions induced by CRS. Second, CRS treatment exhibited a decrease of cGMP content and an increase of cAMP content with marked time-dependent changes, and a high cAMP/cGMP ratio in mice gastric mucosa. Third, pretreatment with 0.25 microg/kg or 0.5 microg/kg dibutyryl cGMP (db-cGMP) exhibited protective effects on CRS-induced gastric lesions, with preventive ratios of 24.61% and 35.32%, respectively. Moreover, db-cGMP at 0.5 microgg/kg significantly attenuated the increase in both cAMP content and the cAMP/cGMP ratio in CRS-treated gastric mucosa. In contrast, db-cAMP exhibited no protective effect, and significantly decreased cGMP content and increased the cAMP/cGMP ratio. These results suggest that EAAs significantly reduce CRS-induced gastric ulcers in mice. The possible mechanism of the antiulcer activity of EAAs may be related to a decrease in the cAMP content in the gastric mucosa of mice. In addition, an increase of the cAMP/cGMP ratio significantly involved in CRS-induced gastric ulcer formation in mice.

Topics: Animals; Cyclic AMP; Cyclic GMP; Excitatory Amino Acids; Male; Mice; Mice, Inbred ICR; Stomach Ulcer; Stress, Physiological; Temperature

To examine the mechanism of stress ulcers and the relation between endothelium derived relaxing factor (EDRF)/NO and gastric mucosal blood flow (GMBF), we used an isolated perfused rat stomach model and studied the effects of an autonomic nerve activator, nitric oxide synthase (NOS) synthesis, and an EDRF/NO inhibitor on gastric blood circulation. Rats were divided into four groups according to pretreatment: (1) control; (2) those given gossypol, a drug provoking endothelial cell damage; (3) those given L-N monomethylarginine (L-NMMA), a specific inhibitor of EDRF/NO; and (4) those subjected to water-immersion stress. Using this model we collected the perfusion fluid from the portal vein at various time points. After administration of acetylcholine, the perfusion flow increased in the control group, but perfusion flow showed no change in the L-NMMA group. On the other hand, the perfusion flow decreased in the gossypol and water-immersion stress groups. The perfusion fluid from the control group contained cGMP, but this substance was absent in the perfusion fluid of the other experimental groups. We considered that increased cGMP in the fluid came from endothelial cells. We presume that the presence of EDRF/NO is essential for the control of GMBF and that from the viewpoint of gastric ulcers, the lack of EDRF/NO may be an important factor in the decrease of GMBF in the early stages of water-immersion stress.

Topics: Acetylcholine; Animals; Blood Flow Velocity; Cyclic GMP; Disease Models, Animal; Endothelium, Vascular; Enzyme Inhibitors; Gastric Mucosa; Gossypol; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type I; Nitroprusside; Rats; Stomach; Stomach Ulcer; Stress, Physiological; Vasodilator Agents

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.

Topics: Animals; Anti-Ulcer Agents; Cimetidine; Cyclic AMP; Cyclic GMP; Epoprostenol; Female; Indomethacin; Rats; Rats, Wistar; Stomach Ulcer; Stress, Psychological

It was published earlier that during gastric ulceration an elevation in the antral and fundic mucosal cAMP/cGMP ratios can be encountered in rats. This phenomenon was interpreted as a probable sign of the reparative, antiulcerogenic processes. This assumption received further evidence when the experimental animals were treated with prostacyclin. According to the present investigations the H2-receptor blocker cimetidine, in such small dose which does not interfere with the gastric acid secretion, evoked the same cAMP/cGMP ratio elevating effect. On the basis of the performed investigations the questions raised, namely: Does the cytoprotective (anti-ulcerogenic) effect of different drugs have a common molecular basis in the (rat) gastric mucosa? If so, what is the possible role of the mucosal cyclic nucleotides in this process? Further studies are being needed in this field to clarify all details.

Topics: Analysis of Variance; Animals; Cimetidine; Cyclic AMP; Cyclic GMP; Epoprostenol; Female; Gastric Acid; Gastric Fundus; Gastric Mucosa; Pyloric Antrum; Radioimmunoassay; Rats; Rats, Inbred Strains; Stomach Ulcer

Topics: Actihaemyl; Adult; Cyclic AMP; Cyclic GMP; Drug Evaluation; Duodenal Ulcer; Female; Gastrins; Humans; Insulin; Male; Middle Aged; Stomach Ulcer; Tissue Extracts

Topics: Animals; Cyclic AMP; Cyclic GMP; Epoprostenol; Gastric Fundus; Gastric Mucosa; Indomethacin; Pyloric Antrum; Rats; Rats, Inbred Strains; Stomach Ulcer; Stress, Physiological

The experiments on rats have proved that ulcerative lesions in the gastric mucosa influenced by intraperitoneal catecholamines (noradrenaline and adrenaline) develop on the background of pronounced decrease of cAMP level in the gastric mucosa during ulceration and relatively slight fluctuations of cGMP level. As a result, cAMP/cGMP ratio in mucosa was significantly decreased during ulceration. These changes in cAMP level and cAMP/cGMP ratio may play an important role in destabilization of lysosomal membranes followed by a chain of pathological reactions resulting in ulcerative lesions of the gastric mucosa.

Topics: Animals; Cyclic AMP; Cyclic GMP; Epinephrine; Female; Gastric Mucosa; Injections, Intraperitoneal; Lysosomes; Male; Norepinephrine; Rats; Stomach Ulcer; Time Factors

In both ulcer models investigated, except the 240-min IND and 8-hr STR cAMP values in the antrum, the cyclic nucleotides showed a significant decrease in the gastric mucosa, which is most probably a sign of cellular exhaustion.

Topics: Animals; Cyclic AMP; Cyclic GMP; Disease Models, Animal; Female; Gastric Fundus; Gastric Mucosa; Indomethacin; Pyloric Antrum; Rats; Rats, Inbred Strains; Stomach Ulcer; Stress, Physiological

Topics: Adult; Aged; Cyclic AMP; Cyclic GMP; Female; Gastric Mucosa; Humans; Male; Medicine, Chinese Traditional; Metaplasia; Middle Aged; Splenic Diseases; Stomach Neoplasms; Stomach Ulcer

Topics: Animals; Cyclic AMP; Cyclic GMP; Male; Plant Extracts; Plants, Medicinal; Rats; Rats, Inbred Strains; Rheum; Stomach Ulcer; Stress, Physiological

Topics: Animals; Cyclic AMP; Cyclic GMP; Gastric Mucosa; Male; Rats; Stomach Ulcer; Stress, Physiological

In female rats aspirin-induced gastrin mucosal damage was increased and glycoprotein synthesis decreased by fasting and by insulin administration. Glucose added to the drinking water during the fasting period reduced mucosal damage and increased glycoprotein synthesis to control levels. Alloxan diabetes did not affect mucosal damage or glycoprotein synthesis. Alloxan diabetes plus insulin restored blood glucose levels to normal, and susceptibility to aspirin damage and glycoprotein synthesis were also normal. Alloxan diabetes plus fasting restored blood glucose levels to normal but increased aspirin-induced mucosal damage and reduced glycoprotein synthesis. In vitro incubation of gastric mucosal homogenates showed that diburyryl cyclic AMP and theophylline inhibited glycoprotein synthesis but dibutyryl cyclic GMP had no significant effects. The importance of an adequate supply of glucose to the gastric mucosa and the effects of cyclic nucleotides on glycoprotein synthesis are discussed.

Topics: Adrenal Cortex Hormones; Animals; Aspirin; Blood Glucose; Bucladesine; Cyclic AMP; Cyclic GMP; Diabetes Mellitus, Experimental; Dibutyryl Cyclic GMP; Fasting; Female; Gastric Mucosa; Glucosamine; Glycoproteins; Hypoglycemia; Insulin; Rats; Stomach Ulcer