nitroarginine and Stomach-Ulcer

Pioglitazone, a specific ligand for peroxisome proliferator-activated receptor gamma (PPAR-gamma), was recently implicated in the control of inflammatory processes and in the modulation of the expression of various cytokines such as tumor necrosis factor alpha (TNF-alpha), but its role in the mechanism of gastric mucosal integrity has not been studied extensively. This study was designed to determine the effect of pioglitazone on gastric mucosal lesions induced in rats by topical application of 100% ethanol and by 3.5 h of water immersion and restraint stress (WRS) with or without pretreatment with indomethacin (5 mg/kg i.p.) to inhibit cyclooxygenase-1 (COX-1) and COX-2 enzyme activities and L-NNA (20 mg/kg i.p.) to suppress nitric oxide (NO)-synthase. In addition, the effect of pioglitazone on ulcer healing in rats with chronic acetic acid ulcers (ulcer area 28 mm2) was determined. Rats were killed 1 h and 3.5 h after ethanol administration or WRS exposure or at day 9 upon ulcer induction, and the number and area of gastric lesions were measured by planimetry, the gastric blood flow (GBF) was determined by H2-gas clearance technique and the mucosal PGE2 generation and gene expression and plasma concentration of TNF-alpha and IL-1beta were also evaluated. Pre-treatment with pioglitazone dose-dependently attenuated gastric lesions induced by 100% ethanol and WRS; the dose reducing these lesions by 50% (ID50) being 10 mg/kg and 7 mg/kg, respectively. The protective effect of pioglitazone was accompanied by the significant rise in the GBF, an increase in PGE2 generation and the significant fall in the plasma TNF-alpha and IL-1beta levels. Strong signals for IL-1beta- and TNF-alpha mRNA were recorded in gastric mucosa exposed to ethanol or WRS, and these effects were significantly decreased by pioglitazone. Indomethacin which suppressed PG generation by about 90%, while augmenting WRS damage, and L-NNA, that suppressed NO-synthase activity, significantly attenuated the protective and hyperaemic activity of this PPAR-gamma ligand. In the chronic study, pioglitazone significantly reduced the area of gastric ulcers on day 9 and significantly raised the GBF at the ulcer margin. The acceleration of ulcer healing by PPAR-gamma ligand was accompanied by a significant increase in the expression of PECAM-1 protein, a marker of angiogenesis. We conclude that (1) pioglitazone exerts a potent gastroprotective and hyperaemic actions on the stomach involving endogenous PG

Topics: Animals; Anti-Ulcer Agents; Blood Flow Velocity; Blotting, Western; Dinoprostone; Dose-Response Relationship, Drug; Enzyme Inhibitors; Ethanol; Gastric Mucosa; Gene Expression; Indomethacin; Interleukin-1; Male; Nitric Oxide Synthase; Nitroarginine; Pioglitazone; Platelet Endothelial Cell Adhesion Molecule-1; PPAR gamma; Rats; Rats, Wistar; Restraint, Physical; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Stomach Ulcer; Thiazolidinediones; Tumor Necrosis Factor-alpha; Wound Healing

The influence of verapamil on stress-induced and histamine-induced gastric ulcers was investigated in rats. The influence of verapamil was also examined on various biochemical parameters that affect the development of these ulcer models. The animals were pretreated with intraperitoneal verapamil (1, 5, 25 mg/kg) by injection 1 h before the induction of experimental ulceration. The gastric lesions were induced by cold-restraint stress or intraperitoneal injection of histamine (300 mg/kg). The gastroprotective effects of verapamil were evaluated by determining the ulcer index, gastric mucus content, free and total acidity, lipid peroxidation and non-protein sulfhydryl content. Verapamil pretreatment at a dose of 25 mg/kg significantly reduced stress-induced ulcers. Verapamil enhanced mucus secretion, reduced total acidity and lipid peroxidation and decreased non-protein sulfhydryl content in a dose-dependent fashion. On the other hand, pretreatment with verapamil at any dose had no significant effect on histamine-induced ulcers. L-Arginine (L-A) (100 mg/kg) or L-nitroarginine (L-NNA) (100 mg/kg) were also injected i.p. to the animals 1 h before stress to test the role of nitric oxide (NO) in the mechanism of the gastroprotective activity of verapamil (25 mg/kg). The results suggested that verapamil stimulates gastric NO production, but the overproduction of NO worsens gastric ulcers. The effects of verapamil on experimentally induced ulcers may be related to its ability to induce biochemical alterations in the parameters measured in gastric tissue.

Topics: Animals; Arginine; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Evaluation, Preclinical; Drug Therapy, Combination; Gastric Acidity Determination; Gastric Mucins; Gastric Mucosa; Histamine; Injections, Intraperitoneal; Lipid Peroxidation; Nitroarginine; Rats; Stomach Ulcer; Stress, Physiological; Sulfhydryl Compounds; Verapamil

Leptin was shown to exhibit similar to cholecystokinin (CCK) cytoprotective activity against acute gastric lesions, but its role in ulcer healing has not been examined. The aims of this study were: (1) to compare the effects of exogenous leptin to those of CCK on the course of healing of chronic gastric ulcers; (2) to study the gene and protein expression of leptin at the ulcer margin during ulcer healing; and (3) to assess the effects of leptin administration on the mucosal gene expression of main growth factor such as transforming growth factor alpha (TGFalpha). Gastric ulcers were produced in rats by the acetic acid method. Rats with ulcers were divided in following treatment groups: (1) vehicle; (2) leptin (10 microg/kg i.p.); (3) CCK (10 microg/kg s.c.); and (4) leptin or CCK with or without tyrphostin A46 (200 microg/kg i.p.), an inhibitor of epidermal growth factor (EGF)-receptor tyrosine kinase or NG-nitro-L-arginine (20 mg/kg i.g.), a blocker of nitric oxide synthase. Animals were euthanized 9 days after ulcer induction. The area of gastric ulcers and the gastric blood flow at the ulcer area were determined. In addition, mucosal biopsy samples were taken from the ulcer area for histological evaluation as well as for the determination of mRNA and protein expression for leptin and constitutive nitric oxide synthase (cNOS) and inducibile nitric oxide synthase (iNOS) by reverse-transcriptase polymerase chain reaction (RT-PCR) and Western blot, respectively. In addition, the gene expression for TGFalpha was analyzed by RT-PCR. Both leptin and CCK reduced significantly the ulcer area as compared to vehicle-treated group by approximately 50%. The treatment with tyrphostin or N(G)-nitro-L-arginine reversed in part the acceleration of ulcer healing by leptin and CCK. The expression of leptin mRNA and protein was significantly increased at the ulcer edge. The leptin-induced acceleration of ulcer healing was associated with increased expression of transcripts for TGFalpha as well as increased mRNA and protein expression for cNOS and iNOS at the ulcer margin. We conclude that leptin accelerates ulcer healing by mechanisms involving the up-regulation of TGFalpha and increased production of nitric oxide due to up-regulation of cNOS and iNOS in the ulcer area.

Topics: Animals; Enzyme Inhibitors; Gastric Mucosa; Gastrointestinal Agents; Leptin; Male; Nitric Oxide Synthase; Nitric Oxide Synthase Type I; Nitric Oxide Synthase Type III; Nitroarginine; Rats; Rats, Wistar; RNA, Messenger; Sincalide; Stomach Ulcer; Transforming Growth Factor alpha; Tyrphostins

CCK exhibits a potent cytoprotective activity against acute gastric lesions, but its role in ulcer healing has been little examined. In this study we determined whether exogenous CCK or endogenously released CCK by camostate, an inhibitor of luminal proteases, or by the diversion of pancreatico-biliary secretion from the duodenum, could affect ulcer healing. In addition, the effects of antagonism of CCK-A receptors (by loxiglumide, LOX) or CCK-B receptors (by L-365,260), an inhibition of NO-synthase by N(G)-nitro-L-arginine (L-NNA), or sensory denervation by large neurotoxic dose of capsaicin on CCK-induced ulcer healing were examined. Gastric ulcers were produced by serosal application of acetic acid and animals were sacrificed 9 days after ulcer induction. The area of ulcers and blood flow at the ulcer area were determined. Plasma levels of gastrin and CCK and luminal somatostatin were measured by RIA and mucosal biopsy samples were taken for histological evaluation and measurement of DNA synthesis. CCK given s.c. reduced dose dependently the ulcer area; the threshold dose of CCK being 1 nmol/kg and the dose inhibiting this area by 50% being 5 nmol/kg. This healing effect of CCK was accompanied by a significant increase in the GBF at ulcer margin and the rise in luminal NO production, plasma gastrin level and DNA synthesis. Concurrent treatment with LOX, completely abolished the CCK-8-induced acceleration of the ulcer healing and the rise in the GBF at the ulcer margin, whereas L-365,260 remained without any influence. Treatment with camostate or diversion of pancreatic juice that raised plasma CCK level to that observed with administration of CCK-8, also accelerated ulcer healing and this effect was also attenuated by LOX but not by L-365,260. Inhibition of NO-synthase by L-NNA significantly delayed ulcer healing and reversed the CCK-8 induced acceleration of ulcer healing, hyperemia at the ulcer margin and luminal NO release, and these effects were restored by the addition to L-NNA of L-arginine but not D-arginine. Capsaicin denervation attenuated CCK-induced ulcer healing, and the accompanying rise in the GBF at the ulcer margin and decreased plasma gastrin and luminal release of somatostatin when compared to those in rats with intact sensory nerves. Detectable signals for CCK-A and B receptor mRNAs as well as for cNOS mRNA expression were recorded by RT-PCR in the vehicle control gastric mucosa. The expression of CCK-A receptor mRNA and cNOS mRNA wa

Topics: Animals; Cholecystokinin; DNA Replication; Dopamine Agents; Esters; Gabexate; Gastric Mucosa; Gastrins; Guanidines; Hormone Antagonists; Male; Nitric Oxide; Nitric Oxide Synthase; Nitroarginine; Pancreatin; Proglumide; Protease Inhibitors; Rats; Rats, Wistar; Receptors, Cholecystokinin; Regional Blood Flow; RNA, Messenger; Sensory Receptor Cells; Sincalide; Somatostatin; Stomach; Stomach Ulcer

Lafutidine is a new type antiulcer agent with antisecretory and gastroprotective activities. We investigated the effect of lafutidine on indomethacin-induced antral ulcer in refed rats. Subcutaneous indomethacin injection resulted in the formation of gastric antral ulcer. Lafutidine (1-10 mg/kg, p.o.) reduced the area of ulcer in a dose-dependent manner when administered immediately after the indomethacin injection. Capsaicin at 3 mg/kg, p.o. and 16,16-dimethyl prostaglandin E2 at 3 microg/kg, p.o. also reduced the ulcer area. Chemical deafferentation of capsaicin-sensitive neurons or N(G)-nitro-L-arginine treatment aggravated the ulcer formation and abolished the preventive effect of lafutidine and capsaicin. After the induction of gastric ulcer, lafutidine given twice daily for 2.5 days reduced the area of ulcer in a dose-dependent manner with a significant effect at 10 mg/kg, p.o., as compared with that of the control group. In chemically-deafferentated rats, lafutidine did not show any healing effect. Cimetidine (30 mg/kg, p.o.) and famotidine (1 mg/kg, p.o.) had no significant effect on indomethacin-induced antral ulcer. These results may suggest that lafutidine, unlike cimetidine and famotidine, can prevent the indomethacin-induced antral ulcer formation and accelerate the healing of the ulcer in refed rats through mechanisms involving the capsaicin-sensitive afferent neurons and nitric oxide.

Topics: 16,16-Dimethylprostaglandin E2; Acetamides; Administration, Oral; Animals; Anti-Ulcer Agents; Capsaicin; Cimetidine; Denervation; Dose-Response Relationship, Drug; Enzyme Inhibitors; Famotidine; Food; Indomethacin; Male; Nitroarginine; Piperidines; Pyloric Antrum; Pyridines; Rats; Rats, Sprague-Dawley; Stomach Ulcer; Wound Healing

Flavonois derived from sophoradine are known to exhibit gastroprotective and ulcer healing properties but the mechanism of these actions are not fully explained. In this study we determined the effect of novel flavonoid derivative of sophoradin, SU-840, on gastric secretion, acute gastric lesions induced by acid-independent (100% ethanol) or acid-dependent ulcerogens (acidified aspirin (ASA) and stress) and on the healing of chronic gastric ulcers in rats. The number and area of gastric lesions was determined by planimetry, gastric blood flow (GBF) was measured using H2-gas clearance technique and the mucosal samples were excised for the measurement of PGE2 generation by radioimmunoassay. Exposure of rats to 100% ethanol or acidified ASA (100 mg/kg dissolved in 0.2 N HCl) or to water immersion and restraint stress (WRS) resulted in hemorrhagic gastric lesions accompanied by drastic fall in the GBF as compared to the values recorded in vehicle treated gastric mucosa. SU-840 (6.25-100 mg/kg i.g.) reduced dose-dependently gastric acid and pepsin secretion and gastric lesions induced by ethanol, acidified ASA and WRS, the dose inhibiting by 50% of these lesions (ID50) being 28, 17 and 95 mg/kg, respectively. This protection required much lower doses as compared to original sofalcone or sucralfate and was obtained when this sofalcone-like drug was administered via parenteral route. The protective effect of SU-840 given i.g. or i.p. was accompanied by a marked rise in the GBF and mucosal generation of PGE2. The protective activity of SU-840 showed longer duration of the action than that of sofalcone and occurred in the doses that failed to affect gastric secretion. Pretreatment with indomethacin to suppress endogenous PG reversed completely the protective and hyperemic effects of SU-840 against ethanol and stress induced damage whereas L-NNA, a potent inhibitor of NO-synthase, failed to affect protection but completely abolished the hyperemia evoked by this agent. NEM, an sulfhydryl alkylator, significantly attenuated the protective and hyperemic effects of SU-840 suggesting that endogenous sulfhydryls are involved in these effects. Seven day treatment with SU-840 accelerated significantly healing rate of chronic gastric ulcers and increased the GBF at the ulcer crater and ulcer margin. These effects were reversed by L-NNA and further restored by the addition to L-NNA of L-arginine, a substrate for NO-synthase. We conclude that SU-840 exhibits gastroprotective

Topics: Animals; Anti-Ulcer Agents; Cyclooxygenase Inhibitors; Enzyme Inhibitors; Ethylmaleimide; Female; Flavonoids; Gastric Acid; Indomethacin; Male; Nitroarginine; Rats; Rats, Wistar; Regional Blood Flow; Stomach; Stomach Ulcer; Sucralfate; Wound Healing

Previously we reported that dehydroleucodine (DhL), a sesquiterpene lactone, shows gastric and duodenal cytoprotective activity. The mechanism is not mediated by antiacid secretory action; DhL stimulated mucus production and indomethacin pretreatment reduced cytoprotective action. In the present study we demonstrated that the gastric cytoprotective effect is antagonized by the nitric oxide (NO) synthase inhibitor, NG-nitro-L-arginine. The inhibitory action of NG-nitro-L-arginine is reversed by L-arginine, but not D-arginine. The findings suggest that NO is involved in the gastroprotection induced by DhL.

Topics: Animals; Anti-Ulcer Agents; Arginine; Central Nervous System Depressants; Cyclooxygenase Inhibitors; Enzyme Inhibitors; Ethanol; Female; Indomethacin; Lactones; Male; Nitric Oxide; Nitric Oxide Synthase; Nitroarginine; Rats; Rats, Wistar; Sesquiterpenes; Stomach Ulcer

Topics: Adaptation, Physiological; Animals; Brain; Immersion; Immobilization; Iron; Liver; Male; Nitric Oxide; Nitric Oxide Donors; Nitric Oxide Synthase; Nitroarginine; Nitrogen Oxides; Rats; Rats, Wistar; Stomach Ulcer; Stress, Physiological

CuNSN a bis (2-benzimidazolyl)thiother complex with copper, has been shown to prevent the formation of acute gastric mucosal lesions induced by acetylsalicylic acid and ethanol. In the present study we have investigated the role of NO in CuNSN protection from ethanol-induced gastric damage. For this purpose we have used the inhibitor of NO biosynthesis, NG-nitro-L-arginine (L-NNA) as well as L- or D-arginine. Gastric mucosal damage caused by ethanol was dose-dependently increased by i.v. administration of graded dose of L-NNA. The effect of L-NNA was completely antagonized by the administration of L-arginine while D-arginine did not cause a reduction in the damage. Treatment with CuNSN has shown a significant protection against the damage produced by ethanol. This protection was not reversed by L-NNA and was significant as compared to the corresponding control group. The combination of L-NNA plus L-arginine potentiates this protection. These results suggest that NO synthesis is not involved in the protection afforded by CuNSN.

Topics: Amino Acid Oxidoreductases; Animals; Arginine; Chelating Agents; Ethanol; Male; Nitric Oxide; Nitric Oxide Synthase; Nitroarginine; Organometallic Compounds; Rats; Rats, Sprague-Dawley; Stomach Ulcer

This study was designed to determine the efficacy of L-arginine in healing of gastric ulcers induced by acetic acid and to assess the role of nitric oxide (NO), prostaglandins, gastrin and polyamines in the healing process. Intragastric administration of L-arginine (32.5-300 mg/kg/day) enhanced the healing rate of these ulcers in a dose-dependent manner, while D-arginine (300 mg/kg/day) was not effective. The acceleration of healing by L-arginine was accompanied by a marked increase in gastric blood flow (GBF) at the ulcer margin, and an enhancement of serum gastrin level, mucosal DNA synthesis, and DNA and RNA contents and angiogenesis in the granulation tissue in the ulcer bed. A similar increase in ulcer healing associated with hyperemia at the ulcer margin and enhanced angiogenesis but without alteration in serum gastrin were observed after treatment with glyceryl trinitrate, an NO exogenous supplier. Treatment with NG-nitro-L-arginine (L-NNA), an inhibitor of NO synthase, delayed ulcer healing and this was accompanied by a reduction of GBF at the ulcer margin and in angiogenesis in granulation tissue and by a decrease in serum gastrin level and mucosal growth. Addition of L-arginine to L-NNA restored ulcer healing, hyperemia at the ulcer margin and angiogenesis and prevented the fall in serum gastrin and mucosal growth caused by L-NNA. Pretreatment with indomethacin also delayed ulcer healing and this was reversed by the coadministration of L-arginine. Inhibition of polyamine biosynthesis by difluoro-methyl-ornithine completely abolished the acceleration of the healing and the increase in mucosal growth induced by L-arginine. Our findings indicate that L-arginine accelerates ulcer healing due to its hyperemic, angiogenic and growth-promoting actions, possibly involving NO, gastrin and polyamines.

Topics: Animals; Arginine; Chronic Disease; Cyclooxygenase Inhibitors; Dose-Response Relationship, Drug; Eflornithine; Gastrins; Indomethacin; Nitric Oxide; Nitric Oxide Synthase; Nitroarginine; Nitroglycerin; Polyamines; Prostaglandins; Rats; Rats, Wistar; Regional Blood Flow; Stomach; Stomach Ulcer; Vasodilator Agents

Sucralfate is known to protect gastric mucosa against the damaging action of strong irritants and to accelerate healing of chronic ulcers, but the mechanisms underlying these effects have not been elucidated. Similar gastroprotective and healing effects can be obtained with exogenous donors of nitric oxide (NO) and prostaglandins (PG).. The area of gastric lesions was measured by planimetry. Gastric blood flow was determined using laser Doppler flowmetry. The role of NO in the prevention of ethanol-induced gastric damage and in the healing of gastric ulcerations by sucralfate and nocloprost, a stable PGE2 analog, was therefore assessed.. Pretreatment with NG-nitro-L-arginine (L-NNA), an inhibitor of NO synthase, enhanced ethanol-induced mucosal damage and reduced dose-dependently the gastroprotective and hyperemic effects of sucralfate. The doses of L-NNA attenuating significantly the protective effects of sucralfate were 25-50 mg/kg. The effects of L-NNA were reversed by the addition of L-arginine but not D-arginine. For comparison, the gastroprotective (but not hyperemic) effects of nocloprost were not affected by the pretreatment with L-NNA and/or arginine. Daily treatment with L-NNA (50 mg/kg per day) prolonged the healing of chronic gastric ulcers and significantly reduced the acceleration of healing by sucralfate.. We conclude that (i) the gastroprotective and hyperemic effects of sucralfate involve, at least in part, the NO-arginine pathway, (ii) the ulcer healing effects of sucralfate may also involve NO, probably through the hyperemia around the ulcer, and (iii) NO is not essential for the mucosal protection of PGE2 analog, but may account for the gastric vasodilatory effect of this PG.

Topics: Animals; Anti-Ulcer Agents; Arginine; Dose-Response Relationship, Drug; Ethanol; Gastric Mucosa; Laser-Doppler Flowmetry; Male; Nitric Oxide; Nitroarginine; Prostaglandins F, Synthetic; Rats; Rats, Wistar; Stomach Ulcer; Sucralfate; Vasodilator Agents

Cholecystokinin-8 and pentagastrin protect against ethanol-induced gastric mucosal lesions in rats. The protective effect is antagonized by the nitric oxide (NO) synthase inhibitor, NG-nitro-L-arginine. The inhibitory action of NG-nitro-L-arginine is reversed by L-arginine, but not D-arginine. The findings suggest that NO is involved in the gastroprotection induced by both peptides.

Topics: Animals; Anti-Ulcer Agents; Arginine; Ethanol; Gastric Mucosa; Male; Nitric Oxide; Nitroarginine; Pentagastrin; Rats; Rats, Wistar; Sincalide; Stomach Ulcer

Morphine in a dose of 1 mg/kg s.c. decreased mucosal lesions induced by 100% ethanol or acidified aspirin by 79% and 85%, respectively, in rats. When the animals were pretreated with NG-nitro-L-arginine (40 mg/kg i.v.), the mucosal lesions were aggravated in both tests and the gastroprotective action of morphine decreased to 17% and 20%, respectively. This decrease in morphine protection was antagonized by L-arginine but not by D-arginine in the case of ethanol-induced lesions; however, L-arginine failed to restore the gastroprotective effect of morphine when the mucosal damage was induced by acidified aspirin. The protective action of either prostaglandin E2 (0.1 mg/kg orally) or cysteamine (50 mg/kg orally) was not influenced by NG-nitro-L-arginine (L-NNA). When L-NNA was given simultaneously with either indomethacin (10 mg/kg p.o.) or N-ethyl-maleimide (50 mg/kg s.c.), compounds which also reduced the gastroprotective action of morphine, almost complete inhibition of the gastroprotective action of morphine against 100% ethanol-induced lesions was observed as a result of the addition of the inhibitory activities of the latter substances. These results suggest that: (1) Endogenous nitric oxide is likely to be involved in the gastroprotective action of morphine. (2) The protective action of nitric oxide is independent of both mucosal prostaglandins and sulfhydryls.

Topics: Animals; Anti-Ulcer Agents; Arginine; Aspirin; Cysteamine; Dinoprostone; Ethanol; Ethylmaleimide; Female; Gastric Mucosa; Male; Morphine; Nitric Oxide; Nitroarginine; Rats; Rats, Wistar; Stomach Ulcer

We investigated the influence of inhibition of nitric oxide (NO) synthase, using NG-nitro-L-arginine (L-NNA) or NG-mono-methyl-L-arginine (L-NMMA), and the effects of exogenous donor of NO, such as glyceryl trinitrate (GTN), on the healing of chronic gastric ulcers induced by acetic acid, on gastric blood flow around the ulcer and on the number of capillaries in the granulation tissue at the ulcer bed. The inhibition of NO synthase resulted in a delay in ulcer healing and in a reduction in blood flow at the ulcer margin and in the number of capillaries in the granulation tissue at the ulcer bed. These effects of inhibition of NO synthase were antagonized, in part, by the administration of GTN or L-arginine but not D-arginine. We conclude that endogenous NO plays an important role in the maintenance of blood flow around the ulcer, in the angiogenesis in the granulation tissue and, thus, in the healing of gastric ulcers.

Topics: Acetates; Acetic Acid; Amino Acid Oxidoreductases; Animals; Arginine; Gastric Mucosa; Male; Nitric Oxide; Nitric Oxide Synthase; Nitroarginine; Nitroglycerin; omega-N-Methylarginine; Rats; Rats, Wistar; Regional Blood Flow; Stomach; Stomach Ulcer

We investigated the participation of prostaglandins (PG) and nitric oxide (NO) in adaptive cytoprotection using 0.6 N HCl-induced gastric lesions in the rat stomach. Indomethacin reversed the protective effect of 0.2 N HCl more strongly than that of 0.35 N HCl, both of which markedly inhibited HCl ulcer. NG-Nitro-L-arginine (L-NNA) did not affect the protective effect afforded by either 0.2 N HCl or 0.35 N HCl. Combined pretreatment with indomethacin and L-NNA did not diminish the protective action induced by 0.35 N HCl, but almost completely abolished the indomethacin-resistant protection afforded by 0.1 N NaOH. Acid mild irritant increased the gastric fluid volume concentration-dependently, whereas alkaline mild irritant had little or no effect on the volume. These results suggest that: 1) The mediators involved in adaptive cytoprotection afforded by 0.1 N NaOH may be fully ascribed to PG and NO; 2) PG is a major mediator in the protection induced by 0.2 N HCl; 3) In the case of 0.35 N HCl, the mediators remain to be determined since increased gastric fluid volume could contribute to the protection through dilution. These findings thus may indicate that multiple mediators and mechanisms are implicated in adaptive cytoprotection.

Topics: Animals; Arginine; Gastric Mucosa; Indomethacin; Irritants; Male; Nitric Oxide; Nitroarginine; Prostaglandins; Rats; Rats, Sprague-Dawley; Stomach Ulcer

Capsaicin and papaverine are potent vasorelaxants with strong gastroprotective activity against damage induced by absolute ethanol. This protection was originally attributed to the increase in gastric mucosal blood flow (GBF) but the possibility that NO mediates the protective and hyperemic effects of capsaicin and papaverine has been little studied. Using N-nitro-L-arginine (L-NNA), a selective blocker of NO synthase, and L-arginine as a substrate for NO, we investigated the role of NO in protective action of capsaicin and papaverine against ethanol-induced gastric damage and in GBF. Pretreatment with capsaicin (0.1-0.5 mg/kg i.g.) or papaverine (0.1-2 mg/kg i.g.) reduced dose-dependently the area of ethanol-induced lesions, the LD50 being 0.3 and 1 mg/kg, respectively. This protection was accompanied by a gradual increase in the GBF. Intravenous (i.v.) injection of L-NNA (1.2-5 mg/kg), which by itself caused only a small increase in ethanol lesions, reversed dose-dependently the protective and hyperemic effects of capsaicin and papaverine against ethanol-induced damage and attenuated the increase in GBF induced by each of these agents alone. This deleterious effect of L-NNA on the gastric mucosa and the GBF was fully antagonized by L-arginine (200 mg/kg i.v.) but not by D-arginine. L-arginine partly restored the decrease in GBF induced by L-NNA. Pretreatment with indomethacin (5 mg/kg i.p.), which suppressed the generation of PG by 85%, slightly enhanced the mucosal lesions induced by ethanol but failed to affect the fall in GBF induced by this irritant. Gastroprotective and hyperemic effects of capsaicin and papaverine were partly reversed by indomethacin suggesting that endogenous PG are also implicated in these effects. Addition of L-NNA to indomethacin completely eliminated both the protective and hyperemic effects of capsaicin and papaverine. We conclude that both NO and PG contribute to the gastroprotective and hyperemic effects of capsaicin and papaverine on the gastric mucosa.

Topics: Animals; Arginine; Capsaicin; Ethanol; Female; Gastric Mucosa; Indomethacin; Male; Nitroarginine; Papaverine; Rats; Rats, Wistar; Regional Blood Flow; Stomach Ulcer

We investigated the role of nitric oxide (NO) and prostaglandins (PG) in the prevention by sucralfate of ethanol-induced gastric damage and the decrease of gastric blood flow and compared them with those obtained with nocloprost, a potent locally acting gastroprotective agent. Sucralfate and nocloprost given intragastrically (i.g.) protected dose dependently the gastric mucosa against the damage by absolute ethanol and prevented the decrease in blood flow induced by ethanol. Pretreatment with NG-nitro-L-arginine (L-NNA), an inhibitor of NO synthase decreased dose dependently the protection and the maintenance of blood flow provided by sucralfate but not by nocloprost. This decrease of sucralfate protection was antagonized by L-arginine but not D-arginine. Pretreatment with indomethacin also reversed, in part, the protective and hyperemic effects of sucralfate but the combination of both indomethacin and L-NNA completely abolished these effects. We conclude that sucralfate activates both the NO and PG systems that cooperate in the gastroprotective action of this drug and that NO is not involved in the protection induced by a PGE2 analog.

Topics: Animals; Anti-Ulcer Agents; Arginine; Ethanol; Indomethacin; Male; Nitric Oxide; Nitroarginine; Prostaglandins; Prostaglandins F, Synthetic; Rats; Rats, Inbred Strains; Regional Blood Flow; Stomach; Stomach Ulcer; Sucralfate

1. The interactions between carbenoxolone and nitric oxide (NO) were examined by investigating their effects on human platelet aggregation, on rat aortic strips precontracted by phenylephrine and on protection of rat gastric mucosa against ethanol-induced injury. 2. Carbenoxolone (100-300 microM) caused a significant and concentration-dependent potentiation of rat peritoneal neutrophil (RPN)- 3-morpholino-syndnonimine (SIN-1)- or iloprost-induced inhibition of platelet aggregation. Higher concentrations (500 microM) of carbenoxolone alone markedly inhibited platelet aggregation. Pretreatment with carbenoxolone (100-300 microM) antagonized the reversal of the RPN- or SIN-1-induced antiaggregatory effect by oxyhaemoglobin (10 microM). 3. Rat aortic strips with intact endothelium precontracted by phenylephrine (0.1-0.3 microM) were relaxed by carbenoxolone (100-300 microM) in a concentration-dependent manner. Relaxations were abolished by mechanical removal of the endothelium or by incubation with methylene blue (10 microM) or NG-nitro-L-arginine (L-NNA, 100 microM). Sodium nitroprusside (10 nM)-induced relaxations of endothelium-denuded rat aortic strips were potentiated by carbenoxolone (100 microM). . The carbenoxolone (200 mg kg-1, p.o.)-induced gastroprotection against ethanol was antagonized by L-NNA (5-40 mg kg-1) in a dose-dependent manner. Pretreatment of rats with indomethacin (10 mg kg-1, s.c.) increased the effect of L-NNA. 5. The results suggest that the activity of carbenoxolone in the experimental systems tested is due to phosphodiesterase inhibition, although radical scavenging properties of the drug could contribute to some of the effects observed. In the rat gastric mucosa both increased prostaglandin levels and effects on the NO system could contribute to the protective action of carbenoxolone.

Topics: Animals; Aorta; Arginine; Carbenoxolone; Gastric Mucosa; Humans; Iloprost; In Vitro Techniques; Male; Methylene Blue; Molsidomine; Muscle Relaxation; Muscle Tonus; Neutrophils; Nitric Oxide; Nitroarginine; Nitroprusside; Oxyhemoglobins; Rats; Rats, Inbred Strains; Stomach Ulcer; Vasodilator Agents