Masanori Takeeda

Effect of ellagic acid on gastric damage induced in ischemic rat stomachs following ammonia or reperfusion

We examined the effect of ellagic acid (EA), one of the polyphenols that are abundantly contained in whisky as a nonalcoholic component, on gastric lesions induced by ammonia plus ischemia or ischemia/reperfusion in rats, in relation to the antioxidative system. Under urethane anesthesia, a rat stomach was mounted in an ex vivo chamber, and the following two experiments were performed; 1) a stomach was made ischemic (1.5 ml/100 g body weight) for 20 min, followed by reperfusion for 15 min in the presence of 100 mM HCl; 2) a stomach was made ischemic by bleeding from the carotid artery (1 ml/100 g body weight), followed by intragastric application of ammonia (NH4OH: 120 mM). EA (0.1-10 mg/ml) was applied in the chamber 30 min before the onset of ischemia. Gastric potential difference (PD) and mucosal blood flow (GMBF) were measured before, during and after 20 min of ischemia. Ischemia/reperfusion caused a profound drop in GMBF followed by a return, and resulted in hemorrhagic lesions in the stomach in the presence of 100 mM HCI. These lesions were dose-dependently prevented by EA with suppression of lipid peroxidation but no effect on GMBF, and the effect at 6 mg/ml was almost equivalent to that of superoxide dismutase (SOD: 15000 unit/kg/hr) infused i.v. during a test-period. On the other hand, application of NH4OH to the ischemic stomach produced a marked reduction in PD, resulting in severe hemorrhagic lesions. These changes were prevented with both EA and SOD. In addition, EA had a potent scavenging action against monochloramine in vitro. These results suggest that EA exhibits gastric protective action against gastric lesions induced by NH4OH or reperfusion in the ischemic stomach, probably due to its anti-oxidative activity. This property of EA partly explains the less damaging effect of whisky in the stomach and may be useful as the prophylactic for Helicobacter pylori-associated gastritis.

Prevention by Parenteral Aspirin of Indomethacin-Induced Gastric Lesions in Rats Mediation by Salicylic Acid

Nonsteroidal antiinflammatory drugs (NSAIDs) produce gastric damage in experimental animals, irrespective of the route of administration. However, aspirin (ASA) causes damage only when it is given orally. In the present study, we examined the gastric ulcerogenic effect of subcutaneously administered ASA in rats, in comparison with various NSAIDs, and investigated the reason why ASA does not cause damage in the stomach, in relation to its metabolite salicylic acid (SA). Since the antiinflammatory action of SA is known to be mediated, partly, by endogenous adenosine (AD), we also examined the possible involvement of AD in the protective action of SA. Various NSAIDs (indomethacin, flurbiprofen, naproxen, diclrofenac, ASA, SA) were administered subcutaneously, and the gastric mucosa was examined macroscopically 4 hr later. All NSAIDs tested, except ASA and SA, caused hemorrhagic lesions in the stomach, with a marked gastric hypermotility and a decrease of mucosal PGE2 contents. These ulcerogenic and motility responses caused by NSAIDs were blocked by pretreatment with atropine or PGE2. ASA, although inhibiting PGE2 generation, caused neither hypermotility nor damage in the stomach. On the other hand, SA alone inhibited basal gastric motility without any effect on mucosal PGE2 contents, and this agent, when given together with indomethacin, prevented gastric hypermotility and lesion formation in response to indomethacin, without affecting the reduced PGE2 contents. Likewise, ASA inhibited these responses to indomethacin, yet the effects appeared later than those of SA. Following administration of ASA, the blood SA levels reached a peak within 30 min and remained elevated for 4 hr. In addition, the protective effect of SA was not significantly influenced by either the AD deaminase or the AD-receptor antagonists. These results suggest that the failure of parenteral ASA to induce gastric damage may be explained by a protective action of SA metabolized from ASA. SA has a cytoprotective action against NSAID-induced gastric lesions, and this action is not mediated by endogenous AD but may be functionally associated with inhibition of the gastric motility response.

Effect of taurine on ulcerogenic response and impaired ulcer healing induced by monochloramine in rat stomachs

It is well known that neutrophil‐derived hypochlorous acid interacts with ammonia (NH4OH) to generate monochloramine (NH2Cl) and that NH2Cl irritates the gastric mucosa and impairs ulcer healing.

Prostaglandin EP receptor subtypes and gastric cytoprotection

This article reviews recent studies dealing with the relationship between the cytoprotective action of PGE2 and the EP receptor subtypes in the gastric mucosa. Gastric cytoprotection afforded by PGE2 was mimicked by EP1 agonists and attenuated by the EP1 antagonist. Likewise, the adaptive cytoprotection induced by a mild irritant was attenuated by the EP1 antagonist and indomethacin. By contrast, capsaicin-induced protection was mitigated by indomethacin as well as sensory deafferentation but not by the EP1 antagonist. PGE2 failed to provide both direct and adaptive cytoprotection in EP1-receptor knockout mice, while capsaicin-induced protection was observed in the animals lacking either EP1 or EP3 receptors but disappeared in IP receptor knockout mice. We conclude that PGs, either generated endogenously or administered exogenously, exhibit gastric cytoprotection directly through activation of EP1 receptors, and endogenous PGs also contribute to the mucosal protection induced by capsaicin by sensitizing sensory neurons, probably through IP receptors.

Gastric Cytoprotection by Prostaglandin E2 - Relation to EP Receptor Subtypes -

This article overviews our recent studies on the relation between EP receptor subtypes and gastric cytoprotection afforded by endogenous and exogenous PGE2, using rats and EP-receptor knockout mice. Exogenous PGE2 dose-dependently reduced the severity of HCl/ethanol-in-duced gastric lesions. This action of PGE2 was mimicked by another E type prostanoids such as sulprostone (EP1/EP3) and 17-phenyl PGE2 (EP1) but not by butaprost (EP2), ONO-NT-012 (EP3) or 11-deoxy PGEl (EP3/EP4), and significantly attenuated by ONO-AE-829 the selective EP1 antagonist. Similar results were obtained in EP-receptor knockout mice, and PGE2 inhibited these lesions in both wild type and EP3-receptor knockout mice but not in the animals lacking EP1-receptors. HCl/ethanol-induced gastric lesions were also prevented by mild irritants such 20 mM taurocholate (TC). This effect was accompanied by an increase of mucosal PGE2 production, attenuated by indomethacin as well as ONO-AE-829, and disappeared in EP1-receptor knockout mice. On the other hand, capsaicin also protected the stomach against HCl/ethanol, without increase of mucosal PGE2 production. This action was totally attenuated by chemical ablation of afferent neurons, partially mitigated by indomethacin but not by ONO-AE-829. Attenuation by indomethacin of the capsaicin protection was recoverd in the presence of butaprost but not other EP agonists. In addition, capsaicin exihibited gastric protection in knockout mice lacking EP1- and EP3-receptors but not in IP-receptor knockout mice.