Afferent nerve-mediated protection against deep mucosal damage in the rat stomach

Holzer, Peter; Pabst, Maria Anna; Lippe, Irmgard Th.; Peskar, B. M.; Peskar, Bernhard A.; Livingston, Edward H.; Guth, Paul H.

doi:10.1016/0016-5085(90)90005-l

Cited by 187 publications

(84 citation statements)

References 33 publications

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“…It is still controversial whether capsaicin action depends on the presence of endogenous prostaglandins (PGs) (46,47). Our study showed that the protective action of FRG-8813 was abolished by sensory denervation, but not affected by prior administration of indomethacin.…”

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

confidence: 72%

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

confidence: 72%

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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“…ethanol (3,5) and further demonstrated that this agent significantly inhibits gastric motility at the cytoprotective dose, providing more evidence for a relationship between motility inhibition and gastric cytoprotection.…”

Section: Discussionmentioning

confidence: 86%

“…before capsaicin injection. To check for the effectiveness of the treatment, a drop of a 0.1 mg/ml solution of capsaicin was instilled into one eye of each rat, and the protective wiping movements were counted as previously reported (5). Animals treated with capsaicin that showed any wiping movements were excluded from the study.…”

Section: General Protocolsmentioning

confidence: 99%

“…Ablation of these neurons leads to aggravation of gastric lesions in a variety of experimental ulcer models, while intragastric capsaicin protects the rat gastric mucosa against damage induced by various means including ethanol (3)(4)(5). Although Holzer et al (5) suggested that the rise in mucosal blood flow may represent a primary mechanism of afferent nerve-mediated mucosal protection, the pathway underlying this protection is yet undefined.…”

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confidence: 99%

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Gastric motility changes in capsaicin-induced cytoprotection in the rat stomach.

et al. 1991

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ABSTRACT-We have examined the effect of orally administered capsaicin on gastric motility in the rat to investigate a possible relationship between motility change and cytoprotection induced by this agent. Capsaicin, given orally (1-30 mg/kg), dosedependently inhibited hemorrhagic band-like lesions induced by ethanol (60% in 150 mM HQ. This protection was significantly mitigated by desensitization of afferent neurons following capsaicin pretreatment 2 weeks before the experiment, and it was also significantly attenuated by prior administration of indomethacin, but not by spantide. Intragastric administration of capsaicin (30 mg/kg) significantly inhibited gastric motility and increased the mucosal blood flow, but had no effect on the transmucosal potential difference of the stomach. These functional changes induced by capsaicin were also less marked in the afferent neuronal desensitized rat, and they were significantly attenuated by indomethacin but not by spantide. These results suggest that the mucosal protection by intragastric capsaicin may be associated with the inhibition of gastric motility and the increase of mucosal blood flow. These responses may be induced by activation of primary afferent neurons which are probably sensitized by endogenous prostaglandins.

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“…exerted gastroprotective effect against the acidindependent ethanol ulcer model. Moreover, the mucosal protective effect of intravenously injected methanandamide was reversed by the centrally injected CB 1 receptor antagonist SR 141716A, indicating the role of central CB1 receptors in the gastroprotection (Shujaa et al, 2009 (Holzer et al, 1990(Holzer et al, , 1991. (Gyires et al, 2000), nociceptin (Zádori et al, 2008) and substance P (Brancati et al, 2013) Ang II was initially described as a hormone of peripheral origin, the active end product of the renin-angiotensin system.…”

Section: Discussionmentioning

confidence: 99%

Angiotensin II-induced activation of central AT1 receptors exerts endocannabinoid-mediated gastroprotective effect in rats

Gyires

Rónai

Zádori

et al. 2014

Molecular and Cellular Endocrinology

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The aim of the present study was to analyze whether angiotensin II via the endocannabinoid system can induce gastric mucosal protection, since transactivation of cannabinoid CB1 receptors by angiotensin AT1 receptor in CHO cells was described. Experimental ulcer was induced by acidified ethanol given orally in male Wistar rats, CB1(+/+) wild type and CB1(-/-) knock out mice. The compounds were administered intracerebroventricularly. It was found, that 1./ Angiotensin II inhibited the ethanol-induced gastric lesions (11.9-191 pmol); the effect of angiotensin II (191 pmol) was inhibited by the CB1 receptor inverse agonist AM 251 (1.8 nmol) and the inhibitor of diacylglycerol lipase (DAGL), tetrahydrolipstatin (0.2 nmol). 2./ Angiotensin II exerted gastroprotection in wild type, but not in CB1(-/-) mice. 3./ The gastroprotective effect of angiotensin II (191 pmol) was reduced by atropine (1 mg/kg i.v.) and bilateral cervical vagotomy. In conclusion, stimulation of central angiotensin AT1 receptors via activation of cannabinoid CB1 receptors induces gastroprotection in a DAGL-dependent and vagus-mediated mechanism.

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Afferent nerve-mediated protection against deep mucosal damage in the rat stomach

Cited by 187 publications

References 33 publications

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

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

Gastric motility changes in capsaicin-induced cytoprotection in the rat stomach.

Angiotensin II-induced activation of central AT1 receptors exerts endocannabinoid-mediated gastroprotective effect in rats

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