Mucosal acid causes gastric mucosal microcirculatory disturbance in nonsteroidal anti-inflammatory drug-treated rats
Introduction
It is known that nonsteroidal anti-inflammatory drugs (NSAIDs) administration leads to a high incidence of inflammation and ulcers in the digestive tract, especially in the stomach. Furthermore, treatment with NSAIDs is suspended in 5% to 15% of patients with rheumatoid arthritis because of gastrointestinal disturbance (Awtry and Loscalzo, 2000, Singh et al., 1996). Therefore, it is considered important to prevent NSAIDs-induced gastric mucosal lesions to avoid any deterioration in quality of life.
A close relationship between NSAID-induced gastric mucosal lesions and gastric microcirculatory disturbance has been suggested in previous papers. Kawano et al. reported that administration of indomethacin to healthy subjects caused a marked reduction in the amount of hemoglobin in the gastric mucosa as well as oxygen saturation of the hemoglobin in the gastric mucosa immediately after administration, while erosive lesions and petechial hemorrhages developed in the ischemic mucosa (Kawano et al., 1996). These authors also suggested that the primary pathology of NSAID-induced acute gastric mucosal damage might be mucosal lesions caused by ischemia.
For the most part, NSAIDs-induced reduction in gastric mucosal blood flow and damage to the gastric mucosa seem to be caused by suppression of the production of mucosal prostaglandin E2 due to an inhibition of cyclooxygenase (COX)-1. However, given that NSAIDs inhibited prostaglandin biosynthesis by more than 95% without causing gastric mucosal damage in rats (Ligumsky et al., 1983), and that NSAIDs do not always cause gastric mucosal damage even when administered at doses sufficient to inhibit prostaglandin biosynthesis in humans (Frezza et al., 2001), the mechanisms of NSAIDs-induced damage cannot be fully explained by the inhibition of prostaglandin E2 biosynthesis alone. In addition, anti-secretory agents such as histamine H2-receptor antagonists may slow the decrease in gastric mucosal blood flow caused by gastric mucosal damaging factors, such as NSAIDs and ethanol (Hata et al., 2005, Kontrurek et al., 1991, Miyata et al., 1991, Segawa et al., 1991). However, although some histamine H2-receptor antagonists have been shown to be likely stimulants of prostaglandin E2 production and to increase blood flow, much about this phenomenon remains unclear, as the these agents have no affinity for the COX enzymes and capsaicin receptors that are responsible for the increase of mucosal prostaglandin E2 and nitric oxide (Nishihara et al., 2002).
Here, to examine the involvement of gastric acid in NSAID-induced decreases in gastric mucosal blood flow, we investigated the effects of 100 mM hydrochloric acid, nearly the concentration of gastric juice, applied to the surface of the gastric mucosa in NSAID-treated rats using a scanning laser Doppler perfusion image system that was able to measure the extensive blood flow in the gastric mucosa.
It is known that, when the mucosa is exposed to ethanol, which is a gastric mucosal damaging factor like gastric acid, vasoconstrictive factors, such as leukotrienes and endothelins, are produced, which in turn cause the gastric mucosal blood flow to decrease drastically (Kawano and Tsuji, 2000, Masuda et al., 1993, Peskar, 1991). For this reason, we also assessed the effect of gastric acid on the amount of vasoconstrictive factors present in the mucosa. Diclofenac and indomethacin were used as typical NSAIDs and celecoxib and rofecoxib as specific COX-2 inhibitors. The potential effect of the differences in COX selectivity among these agents on the effect of gastric acid on gastric mucosal blood flow was tested.
Section snippets
Animals
Eight- to ten-week-old male Sprague-Dawley rats (Charles River Japan, Inc., Yokohama, Japan) were used. The animals were fasted for 18 h prior to the experiments. Water was supplied ad libitum. All animal experimental procedures were performed in accordance with the guidelines of the Animal Experiment Committee of Astellas Pharma Inc.
Drugs
Diclofenac sodium and indomethacin, typical non-specific COX inhibitors, were purchased from Sigma-Aldrich Japan (Tokyo, Japan) and dissolved in physiological
Changes in gastric mucosal blood flow of rats injected with NSAIDs
The time course of changes in blood flow in rats that received saline, diclofenac or indomethacin by subcutaneous injection is shown in Fig. 1. Changes associated with the presence or absence of hydrochloric acid during the acid application period are compared in Fig. 3.
When physiological saline was filled in the chamber, the gastric mucosal blood flow was maintained at a nearly constant level throughout the 90-min measurement period regardless of which drug was injected (Fig. 1A). Blood flow
Discussion
We examined the involvement of mucosal acid in the NSAID-induced decrease in gastric mucosal blood flow by applying acid to the gastric mucosal surface of rats pretreated with typical NSAID or specific COX-2 inhibitors. Our findings indicated that the key factor in NSAID-induced gastric mucosal microcirculatory disturbance is gastric acid itself, and not prostaglandin E2. This disturbance did not occur in the absence of intragastric acid, even when mucosal prostaglandin E2 was depressed by
References (25)
- et al.
NSAIDS and the microcirculation of the stomach
Gastroenterol. Clin. North Am.
(1996) - et al.
Aspirin can inhibit gastric mucosal cyclo-oxygenase without causing lesions in rat
Gastroenterology
(1983) - et al.
Abundance of endothelin-3 in rat intestine, pituitary gland and brain
Biochem. Biophys. Res. Commun.
(1989) - et al.
Studies on the mechanism for the gastric mucosal protection by famotidine in rats
Jpn. J. Pharmacol.
(1991) Role of leukotriene C4 in mucosal damage caused by necrotizing agents and indomethacin in the rat stomach
Gastroenterology
(1991)- et al.
Modifications of capsaicin-sensitive neurons in isolated guinea pig ileum by [6]-gingerol and lafutidine
J. Pharm. Sci.
(2003) - et al.
The role of capsaicin-sensitive sensory neurons in healing of HCl-induced gastric mucosal lesions in rats
Gastroenterology
(1994) - et al.
Role of prostaglandins in maintaining gastric mucus-cell permeability against acid exposure
J. Lab. Clin. Med.
(2004) - et al.
Aspirin
Circulation
(2000) - et al.
The histopathology of non-steroidal anti-inflammatory drug induced gastroduodenal damage: correlation with Helicobacter pylori, ulcers, and haemorrhagic events
J. Clin. Pathol.
(2001)
Famotidine prevents canine gastric blood flow reduction by NSAIDs
Aliment. Pharmacol. Ther.
Cyclo-oxygenase isozymes in mucosal ulcergenic and functional responses following barrier disruption in rat stomachs
Br. J. Pharmacol.
Cited by (28)
Values of natural products to future antiinflammatory pharmaceutical discovery
2021, Inflammation and Natural ProductsHuman disorders associated with inflammation and the evolving role of natural products to overcome
2019, European Journal of Medicinal ChemistryCitation Excerpt :The mentioned drug contains organic acid which prevents the access of AA to the enzyme on active site and stop COX pathway. Despite the outstanding anti-inflammatory action of the NSAIDs their therapeutic practice is limited due to association with severe side effects in gastrointestinal (GI) pathway [108–110]. The acidic nature of NSAIDs caused the mucosal irritation which leads to abdominal destruction by the inhibiting mucosal protective PGE production [111,112].
Development of GI-safe NSAID; Progression from the bark of willow tree to modern pharmacology
2014, Current Opinion in PharmacologyCitation Excerpt :Impairing the mucus-bicarbonate barrier and increased mucosal permeability NSAID inhibits mucus biosynthesis, reduces mucus production, and weakens the surface mucus barrier as well as lowers bicarbonate secretion, resulted in weakened cellular tight junction and increased mucosal permeability [15]. Reduced gastric mucosal blood flow In non-irritant condition, exposure to an irritant results in a rapid increase in mucosal blood flow via sensory afferent neurons, but inhibition of PGE or PGI synthesis by NSAIDs led to reduced gastric blood flow similar in ischemia-reperfusion damages, reached to defective microcirculatory condition.[16]. Retarded epithelial cell restitution Though the precise net outcome of NSAID action on cell proliferation remains unclear, NSAIDs and responsible gene, NSAID-activated gene-1 either confer inferior mucosal integrity or delay the epithelial restitution [17].
Coenzyme Q10: A novel gastroprotective effect via modulation of vascular permeability, prostaglandin E<inf>2</inf>, nitric oxide and redox status in indomethacin-induced gastric ulcer model
2010, European Journal of PharmacologyCitation Excerpt :Non-steroidal anti-inflammatory drugs (NSAIDs) possess rampant therapeutic activities being useful as analgesics, anti-inflammatory and antipyretic agents; however their common side effect is concerned with gastrointestinal pathogenesis, mediated by several mechanisms. NSAIDs exert their gastropathic action systemically and locally, the first entails hypermotility, reduction of mucus, bicarbonate secretion and mucosal blood flow (Garner et al., 1984), as well as microvascular structural disruption (Funatsu et al., 2007). Moreover, NSAIDs increase gastric acid secretion, inhibit nitric oxide level, permit invasion of activated neutrophils along with the production of reactive oxygen species and free radicals, and interfere with the mucosal cell regeneration (Wallace, 2008).
Evaluation of the anti-inflammatory and analgesic activity of Me-UCH9, a dual cyclooxygenase-2/5-lipoxygenase inhibitor
2007, Life SciencesCitation Excerpt :Besides, after administration of Me-UCH9, rats exhibited an important protection on weight loss when compared with the respective control group or with the reference dexamethasone group (data not shown). Cyclooxygenase-1 is a key enzyme for maintaining gastric mucosal integrity (Funatsu et al., 2007; Takeuchi et al., 2006) and inhibition of this enzyme causes gastric mucosal bleeding. In addition, it has been suggested that inhibition of prostaglandin production by NSAIDs would result in an increased formation of leukotrienes and neutrophil infiltration into the digestive tract.
Histological effect of aspirin on the stomach of male albino Swiss mice (Mus musculus)
2020, Iraqi Journal of Science