Cytoprotective Effects of NC-1300 and Omeprazole on HCl⋅Ethanol-Induced Gastric Lesions in Rats

Okabe, Susumu; Awane, Yumiko

doi:10.1254/jjp.42.123

Cited by 65 publications

(32 citation statements)

References 19 publications

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“…This lesion model is often used to determine the cytoprotective property of drugs, as these lesions are not prevented by antisecretory agents but by low doses of prostaglandins (11). Omepr azole is also known to have a cytoprotective action (19,20). We also confirmed the cytoprotective action of omeprazole.…”

Section: Discussionsupporting

confidence: 74%

Pharmacological Analysis of Receptors Involved in the Late, Tachykininergic Contractile Response to Electrical Transmural Stimulation in Isolated Rabbit Iris Sphincter Muscle

Yamaguchi

Aihara

Yamada

et al. 1993

Japanese Journal of Pharmacology

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ABSTRACT-We investigated the effects of the newly synthesized proton pump inhibitor TY-1 1345, (±)-2 [(4-methoxy-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)sulfinyl]-1H-benzimidazole sodium salt, on gastric mucosal proton pump (H+/K+-ATPase) activity, gastric acid secretion and gastro-duodenal lesions in experimental animals. TY-11345 potently inhibited H+/K+-ATPase activity in isolated rabbit gastric mu cosal microsomes; and the inhibitory effect was enhanced under weak acid conditions, the IC50 (concentra tions that inhibit the enzyme activity by 50%) being 5.8 , tM and 9.9 pM at pH 6.0 and pH 7.4, respectively. In Ghosh & Schild rats, intravenous injection of TY-11345 significantly inhibited gastric acid secretion stimulated by tetragastrin; the effect of TY-11345 was twice as potent as that of omeprazole. In pylorus ligated rats, TY-11345 inhibited basal gastric acid secretion by both the intraduodenal and oral routes, with ED50 values of 1.2 and 4.0 mg/kg, respectively. These effects were 9 and 5 times more potent than those of omeprazole, respectively. Moreover, the antisecretory effect of TY-1 1345 persisted for more than 24 hr in pylorus ligated rats. In experimental ulcer models, TY-11345 prevented the formation of water-immersion stress, ethanol or indomethacin-induced gastric lesions and mepirizole-induced duodenal lesions in rats. The antiulcer effects of TY-11345 were 3 to 15 times more potent than those of omeprazole. These results suggest that TY-11345 has potent antisecretory and antiulcer effects which are exerted by suppression of H+/K+-ATPase activity in gastric parietal cells, so that TY-11345 should be useful for the clinical treatment of peptic ulcer diseases.

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Section: Discussionsupporting

confidence: 74%

Pharmacological Analysis of Receptors Involved in the Late, Tachykininergic Contractile Response to Electrical Transmural Stimulation in Isolated Rabbit Iris Sphincter Muscle

Yamaguchi

Aihara

Yamada

et al. 1993

Japanese Journal of Pharmacology

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“…This effect is also found in other proton-pump inhibitors (3)(4)(5). The mechanism of the cytoprotection is, however, not known.…”

mentioning

confidence: 71%

“…The mechanism of the cytoprotection is, however, not known. This effect of proton-pump inhibitors is observed only when the drugs are given intragastrically (2)(3)(4). So, pro ton-pump inhibitors might need to come in contact with gastric contents, especially gastric acid, to induce cyto protection.…”

mentioning

confidence: 99%

Intrathecal Noradrenaline Facilitates and Inhibits the Flexor Reflex Mediated by Group II Afferent Fibers via α1- and α2-Receptors, Respectively

Fukuda

Higuchi

Koike

et al. 1993

Japanese Journal of Pharmacology

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“…Therefore, omeprazole loses the ability to exert a gastroprotective effect in the absence of luminal acid. Although the precise mechanisms of the gastroprotection are not fully understood, Holm (21) showed that the increase in gastric mucosal blood flow was observed only in the case of oral administration, not in the parenteral injection; and Okabe et al (22) suggested that endogenous sulfhydryl compounds are, in part, involved in the mechanisms of the action of omeprazole. Taken together, these results suggest that the gastroprotective action of FRG-8813 on the gastric mucosa is due to some mechanism other than inhibition of acid secretion or histamine H2-receptor antagonism.…”

Section: Studies Of the Gastroprotective Mechanisms Of Frg-8813mentioning

confidence: 99%

Gastroprotective Activity of FRG-8813, a Novel Histamine H2-Receptor Antagonist, in Rats

Onodera

Shibata

Tanaka

et al. 1995

Japanese Journal of Pharmacology

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ABSTRACT-FRG-8813 ((±)-2-(furfurylsulfinyl)-N-[4-[4-(piperidinomethyl)-2-pyridyl]oxy-(Z)-2-butenyl]acetamide) is a novel histamine H2-receptor antagonist with gastric antisecretory and gastroprotective activities. The present study was designed to investigate the property of gastroprotective action. The oral ED50 values for inhibition of mucosal lesions against 1076 NH3-, 60% ethanol in 0.15 N HCl-, 100% ethanol-, 0.6 N HCl-and sodium taurocholate in 0.4 N HCl-induced damage were 3.3, 11.1, 14.9, 23.3 and 23.1 mg/kg, respectively. FRG-8813 was gastroprotective despite pretreatment with omeprazole, suggesting that the protective effect is independent of its antisecretory activity. It is unlikely that FRG-8813 works as a mild irritant because it showed a gastroprotective effect after intraperitoneal injection, but oral administration itself did not influence the rat gastric mucosa. Although pretreatment with indomethacin or N-ethylmaleimide did not affect the gastroprotection of FRG-8813, chemical deafferentation induced by capsaicin abolished the gastroprotection.Furthermore, prior administration of tetrodotoxin, the calcitonin generelated peptide (CGRP) antagonist hCGRP8_37 or N~-nitro-L-arginine attenuated the gastroprotection of FRG-8813 as well as that of capsaicin. In contrast to capsaicin, repeated administration of FRG-8813 neither enhanced the susceptibility of the mucosa to damage nor affected the gastroprotective action of short-term treatment. In conclusion, these results suggest that FRG-8813 has gastroprotective activity independently of acid antisecretory activity and that capsaicin-sensitive nerves may be partially or fully involved in the gastroprotective mechanisms of FRG-8813. Keywords:FRG-8813, Gastroprotection, Histamine H2-receptor antagonist, Capsaicin-sensitive nerve, Antiulcer drug Successful peptic ulcer therapy depends on the restoration of the compromised integrity of the gastroduodenal mucosa by either reducing the aggressive factors or enhancing the defensive process in the mucosa. This has been mainly accomplished by reducing intraluminal acid with an histamine H2-receptor antagonist for more than 10 years. The histamine H2-receptor antagonists are among the most frequently employed drugs worldwide, and their leading position can be explained by their proven high antisecretory potency (1, 2). However, numerous reports showed that the incidence of ulcer relapse after discontinuation of the histamine H2-receptor antagonist reaches the same level as that in patients receiving a placebo (3 -5). From these viewpoints, further improvement in ulcer therapy, with regard to quality of ulcer healing and/or ulcer relapse, might be achieved if the agent could enhance the mucosal defensive capacity in addition to decreasing gastric acid secretion.The property of agents that protect the gastric mucosa against necrotizing agents such as ethanol was defined as so-called "cytoprotection"by Robert et al. (6). Subsequent observations demonstrated that although the gastric cells localized deep in the mu...

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Cytoprotective Effects of NC-1300 and Omeprazole on HCl⋅Ethanol-Induced Gastric Lesions in Rats

Abstract: Abstract-NC-1 300 (10

Cited by 65 publications

References 19 publications

Pharmacological Analysis of Receptors Involved in the Late, Tachykininergic Contractile Response to Electrical Transmural Stimulation in Isolated Rabbit Iris Sphincter Muscle

Pharmacological Analysis of Receptors Involved in the Late, Tachykininergic Contractile Response to Electrical Transmural Stimulation in Isolated Rabbit Iris Sphincter Muscle

Intrathecal Noradrenaline Facilitates and Inhibits the Flexor Reflex Mediated by Group II Afferent Fibers via α1- and α2-Receptors, Respectively

Gastroprotective Activity of FRG-8813, a Novel Histamine H2-Receptor Antagonist, in Rats

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