Nitric oxide synthase induction and intestinal epithelial cell viability in rats

Tepperman, Barry L.; Brown, James F.; Whittle, Brendan J.R.

doi:10.1152/ajpgi.1993.265.2.g214

Cited by 124 publications

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“…Based on the use of inhibitors of NO synthase (Rees et al, 1990;Moore et al, 1990) such as NG-monomethyl L-arginine (L-NMMA) or N0-nitroarginine (L-NOARG), NO has been proposed as a mediator of the non-adrenergic, non-cholinergic (NANC) relaxation of the intestinal smooth muscle, including that of rat or guinea-pig stomach and duodenum and the canine ileo-cecal juction and duodenum (Li & Rand, 1990;Bult et al, 1990;Toda et al, 1990;Desai et al, 1991;Irie et al, 1991). In addition, NO synthase has been located in the myenteric plexus and other neuronal structures of the rat gastro-intestinal tract (Bredt et al, 1990;Belai et al, 1992), although the contribution of the nitrergic neuronal enzyme to the overall NO synthase activity in the gastrointestinal tissues is not yet fully clear (Whittle et al, 1992;Grider et al, 1992; Sanders & Ward, 1992;Tepperman et al, 1993).…”

Section: Introductionmentioning

confidence: 99%

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Impairment of nitrergic‐mediated relaxation of rat isolated duodenum by experimental diabetes

Martínez-Cuesta

Massuda

Whittle

et al. 1995

British J Pharmacology

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Diabetes mellitus is associated with changes in gastrointestinal motility. The effects of experimental diabetes, induced by streptozotocin administration to rats 3–4 weeks previously, on the nitric oxide (NO)‐mediated (nitrergic) relaxation of the duodenum have now been investigated. The non‐adrenergic, non‐cholinergic (NANC) relaxation of the isolated duodenum induced by nicotine (0.3 – 10 μm) or the nicotinic agonist, 1,1‐dimethyl‐4‐phenylpiperazinium (DMPP; 10 μm) was inhibited by the NO synthase inhibitor, NG‐nitro‐l‐arginine (3–100 μm). This nitrergic relaxation induced by nicotine or DMPP of the duodenum from diabetic rats was substantially smaller than that of the tissue from control rats. By contrast, the relaxation of the duodenum from diabetic rats to the NO donor, nitroprusside (0.3–10 μm) was similar to that of control tissue, whereas the relaxation to ATP (0.1–3 μm) was enhanced to a small but significant degree. Incubation of duodenal tissue from control rats at 4°C for 72 h, which leads to neuronal disruption, significantly attenuated the relaxation to nicotine or DMPP whereas the relaxation induced by nitroprusside or ATP was not affected. Comparable cold‐storage did not affect the endothelium‐dependent relaxation of rat aortic rings induced by acetylcholine (0.01–2 μm). The calcium‐dependent NO synthase activity in duodenal tissue, determined by the conversion of radiolabelled l‐arginine to citrulline, was significantly reduced in cold‐stored tissue and in tissue obtained from diabetic rats. These findings in the rat duodenum indicate that a reduction in intestinal NO synthase activity is associated with an impairment of the NANC relaxation. A defect in the intestinal nitrergic innervation could thus contribute to the motility dysfunction observed in diabetes.

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Section: Introductionmentioning

confidence: 99%

“…Preliminary accounts of this work have been presented in abstract form (Whittle et al, 1993;Martinez-Cuesta et al, 1994).…”

Section: Introductionmentioning

confidence: 99%

Impairment of nitrergic‐mediated relaxation of rat isolated duodenum by experimental diabetes

Martínez-Cuesta

Massuda

Whittle

et al. 1995

British J Pharmacology

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“…Subsequently, we have demonstrated that the enterocyte injury caused by C. sakazakii appears to be dependent on the production of NO, as inhibition of inducible NO synthase (iNOS) by small interfering RNA (siRNA) prevented apoptosis of IEC-6 cells (19). Although LPS has been shown to increase iNOS expression in the ileum of mice colonized with bacteria (21,22), no studies to date have addressed how OmpA interaction with intestine induces NO.…”

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confidence: 99%

Recruitment of Dendritic Cells Is Responsible for Intestinal Epithelial Damage in the Pathogenesis of Necrotizing Enterocolitis by Cronobacter sakazakii

Emami

Mittal

Wang

et al. 2011

The Journal of Immunology

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Cronobacter sakazakii is a Gram-negative pathogen associated with the cases of necrotizing enterocolitis (NEC) that result from formula contamination. In a mouse model of NEC, we demonstrate that C. sakazakii infection results in epithelial damage by recruiting greater numbers of dendritic cells (DCs) than macrophages and neutrophils in the gut and suppresses DC maturation, which requires outer membrane protein A (OmpA) expression in C. sakazakii. Pretreatment of intestinal epithelial cell monolayers with supernatant from OmpA+ C. sakazakii/DC culture markedly enhanced membrane permeability and enterocyte apoptosis, whereas OmpA− C. sakazakii/DC culture supernatant had no effect. Analysis of OmpA+ C. sakazakii/DC coculture supernatant revealed significantly greater TGF-β production compared with the levels produced by OmpA− C. sakazakii infection. TGF-β levels were elevated in the intestinal tissue of mice infected with OmpA+ C. sakazakii. Cocultures of CaCo-2 cells and DCs in a “double-layer” model followed by infection with OmpA+ C. sakazakii significantly enhanced monolayer leakage by increasing TGF-β production. Elevated levels of inducible NO synthase (iNOS) were also observed in the double-layer infection model, and abrogation of iNOS expression prevented the C. sakazakii-induced CaCo-2 cell monolayer permeability despite the presence of DCs or OmpA+ C. sakazakii/DC supernatant. Blocking TGF-β activity using a neutralizing Ab suppressed iNOS production and prevented apoptosis and monolayer leakage. Depletion of DCs in newborn mice protected against C. sakazakii-induced NEC, whereas adoptive transfer of DCs rendered the animals susceptible to infection. Therefore, C. sakazakii interaction with DCs in intestine enhances the destruction of the intestinal epithelium and the onset of NEC due to increased TGF-β production.

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“…It was considered that nitric oxide derived by this isoform of NOS was injurious to the gastrointestinal mucosa. 47,48 However, this concept was recently challenged by studies in which a protective effect of iNOS on gastric mucosa injury induced by ethanol,¯urbiprofen or water-immersion-restraint stress was reported. 49±51 Although the protective action of nitric oxide through this isozyme is still uncertain, nitric oxide produced from iNOS in the microvasculature and maintenance of blood ow was proposed.…”

Section: Discussionmentioning

confidence: 99%

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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Nitric oxide synthase induction and intestinal epithelial cell viability in rats

Cited by 124 publications

References 0 publications

Impairment of nitrergic‐mediated relaxation of rat isolated duodenum by experimental diabetes

Impairment of nitrergic‐mediated relaxation of rat isolated duodenum by experimental diabetes

Recruitment of Dendritic Cells Is Responsible for Intestinal Epithelial Damage in the Pathogenesis of Necrotizing Enterocolitis by Cronobacter sakazakii

The ulcer healing effect of protamine sulphate in rat stomach

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