Role of Nitric Oxide in Pathogenesis of Aspirin-Induced Gastric Mucosal Damage in Rats

Abstract

We examined the effect of NO synthase inhibitor on the functional and ulcerogenic responses to aspirin (ASA) in rat stomach. The animals were given ASA (20–80 mM) orally with or without HCl (10–50 mM) and killed 2 h later. N^G-nitro-L-arginine methyl ester (L-NAME) was given i.v. 5 min before aspirin. In the functional study, a rat stomach was mounted on an ex vivo chamber under urethane anesthesia, perfused with saline, and transmucosal potential difference (PD), luminal pH, acid secretion and mucosal blood flow (GMBF) were measured simultaneously. ASA alone caused gastric damage in a dose-related manner; mostly nonhemorrhagic lesions. Pretreatment with L-NAME worsened such lesions and caused severe hemorrhagic lesions. Coadministration of HCl with ASA also potentiated gastric lesions in a concentration-dependent manner, changing nonhemorrhagic into hemorrhagic damage, and the worsening effect of L-NAME disappeared when 80 mM ASA was given together with HCl at >20 mM. In chambered stomachs, the mucosal application of ASA (80 mM, 30 min) caused a marked reduction in PD and a slight decrease in acid secretion, with minimal change in GMBF. L-NAME blocked the reduced acid response following ASA and caused stimulation of acid secretion with no effect on PD and GMBF. These effects of L-NAME were all antagonized by coadministration of L-arginine and significantly mitigated by sensory deafferentation or pretreatment with cimetidine or FPL-52694. These results suggest that (1) intragastric administration of ASA causes a release of NO, which reduces the development of hemorrhagic lesions by decreasing acid secretion, and (2) L-NAME worsens gastric damage by increasing acid secretion in ASA-treated stomachs, the process being dependent on endogenous histamine and sensory neurons.

Assessment of Gastroprotective Potential of <i>Delonix regia</i> (Boj Ex Hook) Raf against Ethanol and Cold Restrain Stress-Induced Ulcer in Rats

“…Prior study has established that neutrophil infiltration into gastric mucosal tissues is involved in the progress of acute gastric mucosal lesions [28]. The accumulation of neutrophil infiltration into the gastric mucosal tissues is estimated by MPO [29]. Furthermore, a reduction in the activity of MPO can be interpreted as a manifestation of the anti-inflammatory activity.…”

Gastroprotective and Antioxidant Effects of Montelukast on Indomethacin-Induced Gastric Ulcer in Rats

“…The MPO assay has had widespread use as an index of neutrophil infiltration in various gastric injuries (23,26,44,45,55,56). As shown in Fig.…”

“…Similarly, lansoprazole and ranitidine also increased MPO activity. It has been reported that the release of MPO from gastric cells is another indication of the degree of ulceration, with NSAIDs such as indomethacin also exerting their effects via inhibition of MPO pathways (23,26,44,45,55,56). Tissue MPO activity is a sensitive and specific marker of acute inflammation and reflects polymorphonuclear cell infiltration into the parenchyma.…”

“…It has been shown that neutrophil infiltration into the gastric mucosal tissues is a critical process in the pathogenesis of a variety of gastric ulcers. A myeloperoxidase (MPO) assay has been in widespread use as an index of neutrophil infiltration in various gastric injuries (22,23).…”

Nitric Oxide Donors and Cardiovascular Agents Modulating the Bioactivity of Nitric Oxide

“…NO has cytoprotective properties 1,46,47 in the stomach and other organs that are derived from its ability to increase local blood flow and to scavenge destructive free radicals. 48,49 New classes of NSAIDs that release NO, called NO-NSAIDs, have been developed and have been shown to be safe and effective alternatives to conventional NSAIDs. 49 -52 These agents are composed of two classes of compounds, one that contains a nitrate ester functionality 50 -52 and one that contains an S-nitrosothiol functionality.…”