Inhibition of nitric oxide synthase delays healing of chronic gastric ulcers

Konturek, Stanisław J.; Brzozowski, Tomasz; Majka, Jolanta; Pytko-Polończyk, Jolanta; Stachura, Jerzy

doi:10.1016/0014-2999(93)90997-v

Cited by 171 publications

(121 citation statements)

References 13 publications

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“…L-arginine, a NOS substrate, has been shown to facilitate gastric ulcer healing by increasing cell regeneration in stomach tissues (31). In addition, inhibition of NOS activity has been shown to intensify the stimulatory effects of NO on gastric mucus synthesis and secretion, to inhibit angiogenesis and to suppress ulcer healing (10,32).…”

Section: Discussionmentioning

confidence: 99%

Protective effect of Acer mono Max. sap on water immersion restraint stress-induced gastric ulceration

Park

Son

et al. 2011

Experimental and Therapeutic Medicine

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Abstract. Acer mono Max. sap (AmMs) is called 'Gol-Li-Su' or 'Go-Lo-Soe' in Korean, which means 'water beneficial to the bones'. It is reported that the sap contains several types of minerals and sugars. In particular, the calcium concentration of the sap is 36.5 times higher than that of commercial mineral water. Apart from its anti-osteoporosis effect, no reports have addressed the biological activities of AmMs against degenerative diseases. In the present study, we investigated whether AmMs alleviates gastric ulcer-related symptoms in a stress-induced mouse model. To assess the effect of AmMs on gastric ulcer-like symptoms, we carried out a water immersion restraint (WIRE) test and found that AmMs has potential in alleviating gastric ulcers in a concentration-dependent manner. These results indicate that the nutritional factors of the sap mitigate the gastric ulcer-related symptoms caused by stress-induced gastric lesions in mice. AmMs-treated mice exhibited a significant decrease in the ulcer index as compared to those treated with omeprazole or L-arginine. To examine one potential mechanism underlying this effect, we performed reverse transcription-polymerase chain reaction to ascertain whether molecular markers were associated with the mitigation of the gastric lesions. Epithelial and/or tissue nitric oxide synthase (NOS) was assessed to determine whether or not the genes were down-regulated dose-dependently by the sap. The levels of these enzymes were found to be lower in the tissue samples treated with AmMs compared with the levels in the control samples. These findings collectively suggest that AmMs significantly protects the gastric mucosa against WIRE stress-induced gastric lesions, at least in part, by alleviating inducible NOS and/or neuronal NOS expression. IntroductionAcute gastric mucosal injury is a serious clinical problem worldwide. The symptoms cause severe gastric ulceritis and, with sustained exposure, eventually lead to gastric cancer. Researchers have developed many in vivo gastric lesion models: the water immersion restraint (WIRE) stress model, the indomethacin-induced model and the ethanol-induced model using animals (1). The WIRE model has previously been used to observe various aspects affecting the formation of and recovery from gastric mucosal lesions, including sulphydryls, prostaglandins, growth factors and polyamines (2). WIRE stress-induced gastric lesions have also been used to study the roles of cell death and gastric acid secretion in ulcerogenesis (3).In general terms, gastric lesions are a disorder of the gastric blockade, which typically protects against cavernous problems caused by hydrogen ions and other toxic substances generated in the lumen (4). One main component of the gastric barrier is gastric microcirculation; a disturbance in gastric mucosal perfusion results in the formation of lesions and ulcers, such as those that present in animal models of ischemic gastric lesions (5). Gastric blood flow is classically controlled by signaling molecules, such as prostagland...

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Section: Discussionmentioning

confidence: 99%

Protective effect of Acer mono Max. sap on water immersion restraint stress-induced gastric ulceration

Park

Son

et al. 2011

Experimental and Therapeutic Medicine

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“…The healing of chronic gastric ulcers in rats is delayed by inhibition of NO synthesis (Konturek et al, 1993). Furthermore, NO synthase inhibition increases intestinal permeability, probably through activation of mucosal mast cells (Kanwar et al, 1994).…”

Section: Discussionmentioning

confidence: 99%

“…Nitric oxide (NO) is protective against endotoxin-induced intestinal damage in the rat (Boughton-Smith et al, 1990;Laszlo et al, 1994) and is also a mediator of gastric protection (Konturek et al, 1993). However, NG-nitro-Larginine methyl ester (L-NAME), an NO synthase inhibitor, prevents castor oil-induced diarrhoea .…”

Section: Introduction Methodsmentioning

confidence: 99%

Dissociation of castor oil‐induced diarrhoea and intestinal mucosal injury in rat: effect of N^G‐nitro‐L‐arginine methyl ester

Capasso

Mascolo

Izzo

et al. 1994

British J Pharmacology

108

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1 Castor oil (2 ml orally) produced diarrhoea in rats 1-7 h after challenge, which was associated with gross damage to the duodenal and jejunal mucosa. 2 The injury was accompanied by release of acid phosphatase into the gut lumen, indicating cellular injury.3 Intraperitoneal injection of the nitric oxide (NO) synth~ase inhibitor N0-nitro-L-arginine methyl ester (L-NAME, 2.5-50 mg kg-' twice), prevented the diarrhoea. The dose of L-NAME (50 mg kg-') completely blocked the diarrhoea but increased the release of acid phosphatase and worsened the gross damage. 4 The NO donating compound, isosorbide-5-mononitrate (IMN, 150 mg kg-' twice) reversed the effects of L-NAME (50 mg kg-') on castor oil-induced diarrhoea, gross damage and acid phosphatase release. 5 The apparent dissociation of the diarrhoeal and intestinal mucosal damaging effects of castor oil suggest that NO has a protective effect on the rat duodenal and jejunal mucosa, but that NO mediates, in part, the diarrhoea effect of this laxative.

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“…Indeed, it had been reported that L-arginine, a substrate for NOS, accelerated ulcer healing and increased angiogenesis in the stomach. 5,6 It is anticipated that nitric oxide is also a pivotal factor for ulcer healing. Our results demonstrated a dose-dependent and signi®cant increase in cNOS activity in the gastric mucosa by protamine sulphate.…”

Section: Discussionmentioning

confidence: 99%

“…The results indicated that L-arginine accelerated ulcer healing and increased gastric angiogenesis, whereas L-NMMA or L-NNA resulted in a delay in ulcer healing and a reduction in the number of capillaries. 5,6 Our preliminary study showed that heparin accelerated gastric ulcer healing in rats. 7 The drug however, prolonged bleeding time, which was detrimental to gastric ulcer formation and its healing.…”

Section: Introductionmentioning

confidence: 96%

The ulcer healing effect of protamine sulphate in rat stomach

1999

Aliment Pharmacol Ther

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INTRODUCTIONProtamine sulphate is known for its neutralizing action on the anticoagulation effect of heparin. Moreover, it was recently reported that protamine sulphate could stimulate the release of endothelium-derived relaxing factor in canine arteries, 1 and also nitric oxide production in porcine carotid artery endothelial cells. 2 It was also involved in the regulation of neuronal nitric oxide synthase (NOS) activity. 3 A protamine sulphateproduced systemic hypotension could be attenuated by nitric oxide inhibition. 4 All these re¯ect a close relationship between the protamine sulphate and nitric oxide and their action on the cardiovascular system. It was reported that nitric oxide is a pivotal factor for gastric ulcer healing. The effect of endogenous nitric oxide on the healing process of gastric ulcer was investigated by using L-arginine, a substrate for NOS, and L-N G -monomethylarginine (L-NMMA) or L-N G -nitroarginine (L-NNA), the inhibitors of NOS. The results indicated that L-arginine accelerated ulcer healing and increased gastric angiogenesis, whereas L-NMMA or L-NNA resulted in a delay in ulcer healing and a reduction in the number of capillaries. 5,6 Our preliminary study showed that heparin accelerated gastric ulcer healing in rats. 7 The drug however, prolonged bleeding time, which was detrimental to gastric ulcer formation and its healing. In order to abolish this side-effect, we used protamine sulphate to neutralize such action, so that it could promote the healing action of heparin. Interestingly, protamine sulphate not only completely neutralized the anticoagulation action of heparin, but also potentiated its ulcer SUMMARY Background: Protamine sulphate has been reported to stimulate nitric oxide production from blood vessels, which is a pivotal factor for gastric ulcer healing. Our preliminary study also showed that protamine sulphate potentiated the ulcer healing effect of heparin. Methods: Male SD rats with acetic acid-induced gastric ulcers were given protamine sulphate (40±80 mg/kg, s.c.) twice daily for 4 or 7 days. L-N G -nitroarginine methyl ester (L-NAME, 5 mg/kg), an inhibitor of nitric oxide synthase (NOS), was given s.c. prior to protamine sulphate (80 mg/kg) treatment. Ulcer healing, angiogenesis, mucosal histological changes, NOS activity and growth factors were determined.

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Inhibition of nitric oxide synthase delays healing of chronic gastric ulcers

Cited by 171 publications

References 13 publications

Protective effect of Acer mono Max. sap on water immersion restraint stress-induced gastric ulceration

Protective effect of Acer mono Max. sap on water immersion restraint stress-induced gastric ulceration

Dissociation of castor oil‐induced diarrhoea and intestinal mucosal injury in rat: effect of N^G‐nitro‐L‐arginine methyl ester

The ulcer healing effect of protamine sulphate in rat stomach

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Inhibition of nitric oxide synthase delays healing of chronic gastric ulcers

Cited by 171 publications

References 13 publications

Protective effect of Acer mono Max. sap on water immersion restraint stress-induced gastric ulceration

Protective effect of Acer mono Max. sap on water immersion restraint stress-induced gastric ulceration

Dissociation of castor oil‐induced diarrhoea and intestinal mucosal injury in rat: effect of NG‐nitro‐L‐arginine methyl ester

The ulcer healing effect of protamine sulphate in rat stomach

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Dissociation of castor oil‐induced diarrhoea and intestinal mucosal injury in rat: effect of N^G‐nitro‐L‐arginine methyl ester