Aggravation of Cold-Restraint Stress–Induced Gastric Lesions in Adjuvant Arthritic Rats: Pathogenic Role of Inducible and Endothelial Nitric Oxide

Abstract

Abstract. It was reported previously that non-steroidal anti-inflammatory drugs (NSAID)-induced gastric damage was markedly aggravated in rats during arthritis, and this response was mediated by the overproduction of nitric oxide (NO) derived from endothelial NO synthase (eNOS) in addition to inducible NO synthase (iNOS). The present study examined the gastric ulcerogenic response to cold-restraint stress in adjuvant arthritic rats, particularly in relation to NO /NOS isozymes. Exposure of normal rats to cold-restraint stress (13°C) produced slight gastric damage 3 h later, but the ulcerogenic response was markedly aggravated in arthritic rats. Pretreatment with N G -nitro-L-arginine methyl ester (L-NAME) (a nonselective inhibitor of NOS) slightly increased the cold-restraint stress-induced gastric lesions in normal rats, but dosedependently prevented the aggravation of these lesions in arthritic rats. The increased ulcerogenic response in arthritic rats was significantly suppressed by 1400W (a selective inhibitor of iNOS) and L-iminoethyl ornithine (L-NIO) (a selective inhibitor of eNOS), but not by N G -propyl-Larginine (L-NPA) (a selective inhibitor of nNOS), and almost totally abolished by the coadministration of 1400W and L-NIO. The mucosal expression levels of eNOS and iNOS but not nNOS mRNAs were enhanced in arthritic rats compared with normal rats. The aggravation of stress-induced gastric lesions in arthritic rats was also significantly suppressed by pretreatment with glutathione. These results suggest that the gastric ulcerogenic response to cold-restraint stress is enhanced in arthritic rats, similar to that induced by NSAIDs, and this phenomenon may be causally associated with the upregulation of eNOS /NO in addition to iNOS /NO.

Neuronal Nitric Oxide Synthase-Derived Nitric Oxide Is Involved in Gastric Mucosal Hyperemic Response to Capsaicin in Rats

“…On the other hand, intravenous injection of 1400W did not affect the resting GMBF or the GMBF increase in response to capsaicin. In agreement with our results, it has been reported that the eNOS was expressed mostly in the vasculature throughout the gastric mucosa in rats, but that expression of iNOS was hardly seen in the gastric mucosa of normal rats by using immunohistochemical analysis [11,12]. These findings support our hypothesis that eNOS/NO plays a role in the resting state of GMBF responses, while iNOS/NO plays no role in the increased GMBF in response to capsaicin.…”

“…L -NIO was also reported to be the most potent inhibitor of the eNOS isoform, with an observed IC 50 value of 0.08 μmol/l, a value approximately 4-fold lower than that observed for iNOS (IC 50 = 0.3 μmol/l) and nNOS (IC 50 = 0.3 μmol/l) isoforms [41]. However, the selectivity of L -NIO is not very high, this agent at a high dose (>30 mg/kg) reportedly suppressed the iNOS isoform as well [12,42]. In addition, it was shown that L -NIO inhibited eNOS activity for 4 h after treatment in vivo [12].…”

“…However, the selectivity of L -NIO is not very high, this agent at a high dose (>30 mg/kg) reportedly suppressed the iNOS isoform as well [12,42]. In addition, it was shown that L -NIO inhibited eNOS activity for 4 h after treatment in vivo [12]. In the GMBF resting state, intravenous injection of L -NIO by itself produced a temporary increase in GMBF, although intravenous injection of NPLA did not affect GMBF.…”

“…Inducible NOS (iNOS) requires a stimulus (cytokines, lipopolysaccharides) for the expression in specific cell types such as macrophages, neutrophils, and epithelial cells. Therefore, it is assumed that eNOS-derived NO contributes to the gastric hyperemic response to capsaicin, although the gastric mucosa has been shown to contain not only eNOS [11,12], but also nNOS [11] and iNOS [13]. Interestingly, Chen and Guth [14] speculated that NO comes from not only endothelium, but also nitroxidergic nerves in the submucosa in the gastric vasodilation response to capsaicin.…”

Mechanism Underlying the Protective Effect of Tempol and Nω-Nitro-L-arginine Methyl Ester on Acoustic Injury: Possible Involvement of c-Jun N-Terminal Kinase Pathway and Connexin26 in the Cochlear Spiral Ligament

“…Nitrotyrosine is a product of tyrosine nitration mediated by reactive nitrogen species such as peroxynitrite anion and nitrogen dioxide (21). It is detected in a number of pathological conditions and is considered a marker of NO-dependent oxidative stress.…”