4-hydroxy-2-nonenal and Stomach-Ulcer

Asymmetric dimethylarginine (ADMA) is an endogenous competitive inhibitor of nitric oxide (NO) synthase known to exert vasoconstriction of vascular bed. The elevation of ADMA has been considered as the cardiovascular risk factor associated with hyperlipidemia, hypercholesterolemia and metabolic syndrome. ADMA is produced by the action of dimethylarginine dimethylaminohydrolase (DDAH), which hydrolyzes ADMA to L-citrulline and dimethylamine. Previous studies have shown that endogenous NO plays an important role in the mechanism of gastric mucosal defense, but the role of ADMA in the pathogenesis of serious clinical entity, such as the acute gastric mucosal injury induced by stress has been little studied. In present study, we determined the effect of intragastric (i.g.) pretreatment with ADMA applied in graded doses ranging from 0.1 up to 20 mg/kg on gastric mucosal lesions induced by 3.5 h of water immersion and restraint stress (WRS). The number of gastric lesions was determined by planimetry and the gastric blood flow (GBF) was assessed by laser Doppler technique. The malondialdehyde and 4-hydroxynonenal (MDA+4-HNE) concentration, as an index of oxygen radical-lipid peroxidation was assessed in the gastric mucosa in rats exposed to WRS with or without ADMA administration. Proinflammatory cytokines IL-1β, TNF-α, superoxide dismutase (SOD) and glutathione peroxidase (GPx) mRNAs in the gastric mucosa and plasma levels of ADMA, IL-1β and TNF-α were analyzed by RT-PCR and ELISA, respectively. The exposure of rats to WRS for 3.5 h produced acute gastric lesions accompanied by a significant rise in the plasma ADMA levels and a significant fall in the GBF, an increase in MDA+4-HNE concentrations and the significant increase in the expression and release of IL-1β and TNF-α. The pretreatment with ADMA, applied i.g. 30 min before WRS dose-dependently, aggravated WRS damage and this effect was accompanied by a further significant fall in the GBF. The ADMA induced exacerbation of WRS lesions and the accompanying rise in the plasma ADMA levels and the fall in GBF were significantly attenuated by concurrent treatment with glyceryl trinitrate (GTN) (10 mg/kg i.g.) in the presence of ADMA. Administration of ADMA resulted in a significant decrease in the expression of SOD and GPx mRNAs and the up-regulation of mRNA for IL-1β and TNF-α followed by an increase in these plasma cytokine levels as compared to respective values observed in vehicle-pretreated animals. We conclu

Topics: Aldehydes; Animals; Arginine; Enzyme Inhibitors; Gastric Mucosa; Glutathione Peroxidase; Interleukin-1beta; Lipid Peroxidation; Male; Malondialdehyde; Nitric Oxide Synthase; Rats; Rats, Wistar; Regional Blood Flow; Restraint, Physical; Stomach Ulcer; Stress, Psychological; Superoxide Dismutase; Tumor Necrosis Factor-alpha

Disturbance of the microcirculation and generation of reactive oxygen species are crucial in producing acute gastric mucosal lesions (AGML). To understand the protective mechanism against mucosal injury and oxidative stress in the stomach, we investigated sequential expression and localization of a product of lipid peroxidation and a chemical mediator of the oxidative response array, 4-hydroxynonenal (HNE), transcriptional factor, NF-E2-related factor (Nrf2), and the inducible heme oxygenase (HO-1) in the injured stomach. AGML was produced by intragastric administration of 0.6 N HCl in male rats. Expression and localization of HNE, Nrf2, and HO-1 were investigated by Western blotting, immunohistochemistry, real-time RT-PCR, and in situ hybridization histochemistry. Mucosal lesions and expression of HNE and HO-1 were assessed by prior treatment with the PGI2 analog beraprast or after sensory denervation by pretreatment with capsaicin. Mucosal lesions were assessed by prior treatment with a HO-1 inhibitor, zinc protoporphyrin (ZnPP). After AGML, increased generation of HNE was observed in the injured mucosa and the surrounding submucosa, followed by nuclear translocation of Nrf2 and upregulation of HO-1 in the macrophages located in the margin of the injured mucosa and in the submucosa. Pretreatment with beraprost attenuated AGML and downregulated the expression of HNE and HO-1, while sensory denervation aggravated AGML and upregulated the expression of HNE and HO-1. Pretreatment with ZnPP also aggravated AGML. The sequential HNE-Nrf2-HO-1 pathway in the gastric mucosal cells and the macrophages is involved in an adaptive mechanism against oxidative stress after AGML.

Topics: Adaptation, Physiological; Aldehydes; Animals; Capsaicin; Cytoprotection; Denervation; Disease Models, Animal; Enzyme Inhibitors; Epoprostenol; Gastric Mucosa; Heme Oxygenase (Decyclizing); Hydrochloric Acid; Lipid Peroxidation; Macrophages; Male; NF-E2-Related Factor 2; Oxidative Stress; Protoporphyrins; Rats; Rats, Wistar; Signal Transduction; Stomach Ulcer

Ablation of sensory nerves impairs healing of gastric ulcers, but the role of free radicals in the healing process has been little studied. The aim of our present investigations was to determine the participation of reactive oxygen species (ROS) in sensory nerve activity during WRS. Experiments were carried out on male Wistar rats and the number of gastric lesions was measured by planimetry. Colorimetric assays were used to determine gastric mucosal levels of malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE), as well as superoxide dismutase (SOD) activity. We found that capsaicin-inactivation of sensory nerves resulted in magnification of gastric mucosal damage induced by the WRS. In this process, oxidative stress occurs, as reflected by an increase of MDA and 4-HNE tissue concentrations (an index of lipid peroxidation), and a decrease of SOD activity, could play an important role. Pentoxyfilline-induced gastroprotection and hyperemia depends upon attenuation of the oxidative stress. This protection and hyperemia were, at least in part, attenuated by ASA. Afferent sensory fibers participate in the pathogenesis of ulcers. Lipid peroxidation plays an important role in this process.

Topics: Afferent Pathways; Aldehydes; Animals; Free Radical Scavengers; Gastric Mucosa; Immersion; Lipid Peroxidation; Male; Malondialdehyde; Oxidative Stress; Pentoxifylline; Rats; Rats, Wistar; Reactive Oxygen Species; Restraint, Physical; Stomach Ulcer; Stress, Physiological; Superoxide Dismutase

Gastric microcirculation plays an important role in the maintenance of the gastric mucosal barrier and mucosal integrity. Sensory nerves are involved in the regulation of mucosal blood circulation and mucosal defense. Therefore, the ablation of these nerves by neurotoxic doses of capsaicin provides the possibility of determination of their role in gastric mucosal integrity. Stress ulceration represents a serious gastric lesions. Results of our previous experiments have indicated that water immersion and restraint stress (WRS) led to increased oxidative metabolism. Ablation of sensory nerves by high doses of capsaicin retards healing of gastric ulcers, but the role of reactive oxygen species (ROS) in the healing process has been little studied. Therefore, the aim of our present investigations was to determine the participation of ROS in sensory nerve activity during WRS. Experiments were carried out on 90 male Wistar rats and the area of gastric lesions was measured by planimetry. Colorimetric assays were used to determine gastric mucosal levels of malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE), as well as superoxide dismutase (SOD) activity. We demonstrated that inactivation of sensory nerves resulted in magnification of gastric mucosal damage induced by the WRS. In this process, oxidative stress, as reflected by an increase of MDA and 4-HNE tissue concentrations (an index of lipid peroxidation), as well as decrease of SOD activity, could play an important role. Aspirin, applied in a low dose, exerts a protective activity, possibly due to its metabolites, which possess the anti-oxidant and ROS scavanging properties. Pentoxyfilline-induced gastroprotection and hyperemia depends upon attenuation of the oxidative stress. This protection and hyperemia were, at least in part, attenuated by ASA.

Topics: Aldehydes; Animals; Capsaicin; Denervation; Dose-Response Relationship, Drug; Gastric Mucosa; Immersion; Injections, Intraperitoneal; Injections, Subcutaneous; Lipid Peroxidation; Male; Malondialdehyde; Neurons, Afferent; Pentoxifylline; Rats; Rats, Wistar; Reactive Oxygen Species; Restraint, Physical; Splanchnic Circulation; Stomach Ulcer; Stress, Physiological; Superoxide Dismutase

The experimental model of acute gastritis such as water immersion restraint (WRS) stress-induced gastric injury is useful tool in examination of pathomechanism of acute gastritis. Nitric oxide (NO) plays an important role in the maintenance of gastric barrier, however, the interaction between reactive oxygen species (ROS) and NO on gastric mucosal integrity has been little studied. The purpose of our present study was to explain the participation of ROS in healing of WRS-induced gastric lesions accelerated by NO. Experiments were carrying out on 120 male Wistar rats. To assess gastric blood flow (GBF) laser Doppler flowmeter was used and the number of gastric lesions was counted in each stomach. The colorimetric assays were used to determine gastric tissue level of malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE), the products of lipid peroxidation by ROS, as well as superoxide dismutase (SOD) activity, the enzyme scavanger of ROS. We demonstrated that 3.5 h of WRS resulted in appearance of acute gastric lesions accompanied by a significant decrease of GBF. Biological effects of ROS were estimated by measuring tissue levels of MDA and 4-HNE, as well as the SOD activity. It was demonstrated that 3.5 h of WRS led to significant increase of mucosal levels of MDA and 4-HNE, and it was accompanied by a decrease of SOD activity. Pretreatment with NO-donors (SIN-1, SNAP, nitroglycerin, NO-ASA) resulted in reduction in gastric lesion number, increment of GBF, decrease of MDA and 4-HNE tissue level and increase of SOD activity. Suppression of ROS plays an important role in the action of NO-donors on healing of acute gastric lesions induced by 3.5 h of WRS. NO-donors caused an attenuation of lipid peroxidation as documented by a decrease of MDA and 4-HNE levels and enhancement of antioxidative properties as evidenced by an increase of SOD activity.

Topics: Aldehydes; Animals; Aspirin; Gastric Mucosa; Lipid Peroxidation; Male; Malondialdehyde; Molsidomine; Nitric Oxide Donors; Nitroglycerin; Rats; Rats, Wistar; Reactive Oxygen Species; Regional Blood Flow; S-Nitroso-N-Acetylpenicillamine; Statistics, Nonparametric; Stomach Ulcer; Stress, Psychological; Superoxide Dismutase

Fresh rice oil protects against gastric ulceration in rats maintained on an impoverished diet, whereas stored oil is ulcerogenic. Rice oil contains ketoaldehydes which are ulcerogenic but their activity is prevented by the presence of antioxidants such as alpha-tocopherol, which is lost on storage. Protection may also be restored by the addition of cysteine. These results in rats in vivo can be duplicated in a rat liver microsomal system in vitro, in which malondialdehyde production is a measure of toxicity. It is proposed that the ulcerogenic activity of rice oil is the direct consequence of the stimulation of endogenous lipid peroxidation due to the lowering of the GSH content in the endoplasmic reticulum by the ketoaldehydes in stored rice oil. A similar mechanism is suggested for the ulcerogenic activity of an impoverished diet which directly lowers the tissue levels of GSH.

Topics: Aldehydes; Animals; Cysteine; Diet; Female; Food Preservation; Lipid Peroxides; Oils; Oryza; Rats; Rats, Inbred Strains; Stomach Ulcer; Vitamin E