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

• Published in: Journal of Pharmacological Sciences Vol. 111; no. 3; pp. 244 - 252
• Main Authors: Kato, Shinichi, Kawahara, Ryoji, Yasuda, Masashi, Amagase, Kikuko, Takeuchi, Koji
• Format: Journal Article
• Language: English; Japanese
• Published: Japan Elsevier B.V 2009; The Japanese Pharmacological Society; Elsevier
• Subjects: Animals; Arthritis, Experimental - complications; Arthritis, Experimental - pathology; Blotting, Western; Cold Temperature; cold-restraint stress; endothelial NO synthase (eNOS); Enzyme Inhibitors - pharmacology; gastric damage; Gastric Mucosa - drug effects; Gastric Mucosa - enzymology; Glutathione - pharmacology; Guanidines - pharmacology; Immunohistochemistry; inducible NO synthase (iNOS); Isoenzymes - biosynthesis; Male; Mycobacterium tuberculosis; NG-Nitroarginine Methyl Ester - pharmacology; nitric oxide (NO); Nitric Oxide Donors - pharmacology; Nitric Oxide Synthase Type II - antagonists & inhibitors; Nitric Oxide Synthase Type II - biosynthesis; Nitric Oxide Synthase Type III - antagonists & inhibitors; Nitric Oxide Synthase Type III - biosynthesis; Rats; Restraint, Physical; Stomach Ulcer - complications; Stomach Ulcer - pathology; Stress, Psychological - complications; Stress, Psychological - enzymology; Stress, Psychological - pathology; Tyrosine - analogs & derivatives; Tyrosine - pharmacology; inducible NO synthase (iNOS); nitric oxide (NO); cold-restraint stress; gastric damage; endothelial NO synthase (eNOS)
• ISSN: 1347-8613; 1347-8648
• DOI: 10.1254/jphs.09203FP

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 NG-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 dose-dependently 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 NG-propyl-L-arginine (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.