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Dejban P, Eslami F, Rahimi N, Takzare N, Jahansouz M, Dehpour AR. Involvement of nitric oxide pathway in the anti-inflammatory effect of modafinil on indomethacin-, stress-, and ethanol -induced gastric mucosal injury in rat. Eur J Pharmacol 2020; 887:173579. [PMID: 32950497 PMCID: PMC7495189 DOI: 10.1016/j.ejphar.2020.173579] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2020] [Revised: 09/14/2020] [Accepted: 09/15/2020] [Indexed: 01/22/2023]
Abstract
Gastric ulcer is a prevalent disease with various etiologies, including non-steroidal anti-inflammatory drugs (NSAIDs), stress conditions, and alcohol, resulting in an inflammatory condition in the gastric mucosa. The aim of this study was to explore the protective effects of modafinil on gastric erosions induced by indomethacin, water-immersion stress, and alcohol in rats and to evaluate the role of nitric oxide (NO) pathway. Animals were allocated to the three experimental models of gastric ulcer – indomethacin (30 mg/kg PO), water-immersion stress, and ethanol (5 ml/kg PO). Induction of gastric ulcer in all models caused an increase in J-score (macroscopic assessment), biochemical markers, including tumor necrosis factor-alpha (TNF-α), interleukin-1beta (IL-1β), and myeloperoxidase (MPO), and microscopic destructions. Administration of modafinil (50 and 100 mg/kg i. p) significantly improved J-score in the indomethacin (P < 0.05) and stress models (P < 0.001). Moreover, the level of TNF-α IL-1β, and MPO was deceased after modafinil administration (P < 0.001). However, modafinil did not have any effects on gastric injury induced by ethanol. In addition, co-administration of L-NAME (a non-specific NO synthase inhibitor) and aminoguanidine (an inducible NO synthase inhibitor) with modafinil significantly neutralized the gastroprotective effect of modafinil in the indomethacin and water-immersion stress groups (P < 0.05, and P < 0.01; respectively), while 7-nitroindazole (a neuronal NO synthase inhibitor) did not show such reversing effects. In conclusion, modafinil possesses gastroprotective effects on the gastric lesions induced by indomethacin and stress, which are probably mediated via the inflammation inhibition and NO pathway modulation.
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Affiliation(s)
- Pegah Dejban
- Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran; Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA
| | - Faezeh Eslami
- Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran; Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Nastaran Rahimi
- Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran; Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Nasrin Takzare
- Department of Anatomy, School of Medicine, Tehran University of Medical Science, Tehran, Iran
| | - Mohamadmostafa Jahansouz
- PERFUSE Study Group, Cardiovascular Division, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Ahmad Reza Dehpour
- Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran; Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
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Abstract
Nitric oxide has been suggested as a contributor to tissue injury in various experimental models of gastrointestinal inflammation. However, there is overwhelming evidence that nitric oxide is one of the most important mediators of mucosal defence, influencing such factors as mucus secretion, mucosal blood flow, ulcer repair and the activity of a variety of mucosal immunocytes. Nitric oxide has the capacity to down-regulate inflammatory responses in the gastrointestinal tract, to scavenge various free radical species and to protect the mucosa from injury induced by topical irritants. Moreover, questions can be raised regarding the evidence purported to support a role for nitric oxide in producing tissue injury. In this review, we provide an overview of the evidence supporting a role for nitric oxide in protecting the gastrointestinal tract from injury.
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Zhang Z, Zhou Y, Zou YY, Wang L, Yang ZC, Guo R, Li D, Peng J, Li YJ. Detrimental effects of nicotine on the acute gastric mucosal injury induced by ethanol: role of asymmetric dimethylarginine. Can J Physiol Pharmacol 2009; 86:835-40. [PMID: 19088804 DOI: 10.1139/y08-093] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
The aim of this study was to determine whether asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase (NOS), is responsible for the detrimental effects of nicotine on ethanol-induced gastric mucosal injury and its underlying mechanisms. Gastric mucosal injury was induced by an injection of ethanol in the stomach in rats. Animals were pretreated with nicotine for 28 days before ethanol injection. The gastric mucosal ulcer index (UI) and the levels of ADMA and NO in gastric juice were determined. In vitro, the cultured mucosal epithelial cells were treated with nicotine in the presence or absence of ethanol. The concentration of ADMA in the culture medium and the ratio of cell apoptosis were measured, and the effect of nicotine or ADMA alone on cell apoptosis was also examined. In rats treated with ethanol, the UI and ADMA levels were increased and the NO level was decreased, and these effects of ethanol were augmented by pretreatment with nicotine. Administration of nicotine alone did not show significant impact on UI, ADMA level, or NO level. In vitro, incubation of human epithelial cells with ethanol induced cell injury accompanied by increased ADMA levels in the culture medium, an effect which was amplified in the presence of nicotine. Similarly, ethanol was able to induce epithelial cell apoptosis that was exacerbated by nicotine. Incubation of epithelial cells with nicotine alone did not induce cell apoptosis, but administration of ADMA alone did induce cell apoptosis. The results suggest that the gastric mucosal injury induced by ethanol is augmented by nicotine, which is related to the increased ADMA level.
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Affiliation(s)
- Zhe Zhang
- Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, No.110 Xiang-Ya Road, Changsha 410078, China
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Qui BS, Mei QB, Liu L, Tchou-Wong KM. Effects of nitric oxide on gastric ulceration induced by nicotine and cold-restraint stress. World J Gastroenterol 2004; 10:594-7. [PMID: 14966924 PMCID: PMC4716987 DOI: 10.3748/wjg.v10.i4.594] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
AIM: Stress induces gastric ulceration in human and experimental animals. People tend to smoke more cigarettes when under stress. Nitric oxide (NO) and nicotine have opposing effects on gastric integrity. The present study examined the possible therapeutic benefit of NO in nicotine-treated rats with stress-induced gastric ulceration.
METHODS: Rats drank a nicotine solution while control rats drank tap water for 20 days. The alkoloid was then replaced by water with or without supplementation of isosorbide dinitrate (NO donor) for an additional 10 days. Isosorbide dinitrate was given twice shortly before experiments (acute) or three times daily by oral gavages for 10 days after the rats stopped drinking nicotine solution. At the end of experiments, ulcer index, gastric adhesion mucus content and MPO activity were measured and analysed.
RESULTS: Nicotine treatment decreased gastric mucus content and intensified stress-induced gastric ulcer. A higher ulcer index persisted even after the rats stopped drinking nicotine solution for 10 days. Acute NO donor showed no benefit on both mucus and ulcer index in nicotine treatment or/and stress condition. Chronic NO donor treatment reversed the worsening action of nicotine in stomach. Stress increased gastric mucosal myeloperoxidase (MPO) activity, which was antagonized by chronic NO treatment. However, nicotine was unlikely to change mucosal MPO activity.
CONCLUSION: The intensifying action of nicotine on stress-induced gastric ulceration persists for 10 days after cessation. Nicotine treatment significantly decreases gastric mucus content that can be restored by chronic NO donor treatment. The present study suggests that NO antagonizes the ulcerogenic action of nicotine through a cytoprotective way.
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Affiliation(s)
- Bo-Sheng Qui
- Departments of Medicine, Environmental Medicine, Microbiology, New York University School of Medicine, 550 First Avenue, MSB 141, New York, New York 10016, USA
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Abstract
Inflammation of the intestinal tract remains a very serious concern in the clinical setting. Unfortunately, to date, the mechanisms underlying many inflammatory conditions such as sepsis or inflammatory bowel diseases are poorly understood and our therapeutic interventions are less than ideal. Over the past decade, an abundance of research has been directed toward the role of nitric oxide (NO) in intestinal inflammation. It has become apparent that NO might have a dichotomous role as both a beneficial and detrimental molecule. Nitric oxide is a weak radical produced from L-arginine via the enzyme nitric oxide synthase (NOS). NOS exists in three distinct isoforms; constitutively (cNOS) expressed neuronal NOS (NOS1 or nNOS) and endothelial NOS (NOS3 or eNOS) or an inducible isoform (NOS2 or iNOS) capable of high production output of NO during inflammation. Constitutively expressed NOS has been shown to be critical to normal physiology and inhibition of these enzymes (nNOS or eNOS) caused damage. It has been proposed that the high output production of NO from iNOS causes injury, perhaps through the generation of potent radicals such as peroxynitrite and hence may explain the apparent dichotomous role of NO. However, recent studies have challenged this simple paradigm providing evidence that iNOS may have some protective role in some inflammatory models. Moreover, the importance of peroxynitrite has been questioned. In this review we discuss the role of cNOS and iNOS in intestinal inflammation and provide an overview of peroxynitrite in intestinal inflammation, highlighting some of the controversy that exists.
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Affiliation(s)
- P Kubes
- Immunology Research Group, Department of Physiology and Biophysics, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada
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Schleiffer R, Raul F. Nitric oxide and the digestive system in mammals and non-mammalian vertebrates. COMPARATIVE BIOCHEMISTRY AND PHYSIOLOGY. PART A, PHYSIOLOGY 1997; 118:965-74. [PMID: 9505415 DOI: 10.1016/s0300-9629(97)00026-1] [Citation(s) in RCA: 21] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The focus of the presentation will review the distribution of nitric oxide (NO)-producing sites in the digestive system in mammals and nonmammalian vertebrates and will center on the roles that NO plays in modulating physiological and pathophysiological functions in digestive system.
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Affiliation(s)
- R Schleiffer
- CJF INSERM 95-09, IRCAD, Hôpitaux Universitaires, Strasbourg, France
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Abstract
Nitric oxide (NO) synthase, the enzyme responsible for NO formation, is located in brain regions such as amygdala and dorsolateral central grey, regions which are known to be involved in anxiety. To investigate the possible role of NO in anxiety, rats received acute i.p. injections of NG-nitro-l-arginine (L-NOARG, 7.5-120 mg kg-1), an inhibitor of NO synthase, and were tested in the elevated plus maze, an animal model of anxiety. The drug, at doses of 30-120 mg kg-1, decreased the percentage of entries and time spent on the open arms of the maze, but these doses, with exception of 30 mg, also decreased the number of entries into enclosed arms. These effects disappeared when the animals were tested after chronic L-NOARG treatment (3.75 to 60 mg kg-1 i.p., twice a day for four days). The effects of acute i.p. injection of 30 mg kg-1 of L-NOARG were blocked by i.c.v. pretreatment with 1000 nmol of l-arginine (but not 500 nmol). Thus, inhibition of NO formation in the central nervous system seems to decrease exploration of the elevated plus maze, an effect that disappears after four days of chronic (twice a day) L-NOARG administration.
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Affiliation(s)
- C L De Oliveira
- Department of Pharmacology, FMRP, Ribeirão Preto, SP, Brazil
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Coskun T, Yeğen BC, Alican I, Peker O, Kurtel H. Cold restraint stress-induced gastric mucosal dysfunction. Role of nitric oxide. Dig Dis Sci 1996; 41:956-63. [PMID: 8625769 DOI: 10.1007/bf02091537] [Citation(s) in RCA: 20] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
The objectives of this study were to determine the cold restraint stress-induced changes in gastric mucosal permeability and to assess whether nitric oxide synthesis inhibition affects gastric mucosal integrity after cold-restraint administration. Cold-restraint stress caused multiple gastric lesions in 90% of animals. The lesion index was found to be 3.87 +/- 0.97 mm. Gastric mucosal permeability to the [51CR]EDTA molecule was significantly elevated in the cold-restraint group compared to control. In order to evaluate the role of nitric oxide in cold restraint stress-induced gastropathy, L-arginine analog NG-nitro-L-arginine methyl ester (L-NAME) was given as a bolus (10 mg/kg, intravenously) and infused at a rate of 2 mg/ml/hr for 2 hr after cold-restraint administration. L-NAME greatly exacerbated gastric mucosal dysfunction associated with cold-restraint stress. D-NAME, the biologically inactive enantiomer, did not enhance mucosal dysfunction, whereas L-arginine, the substrate for nitric oxide, reversed the effect of L-NAME. In an additional group of experiments, effects of cold-restraint stress and L-NAME on net transmucosal fluid flux as well as tissue myeloperoxidase activity (MPO) were assessed. Cold-restraint stress administration significantly reduced the absorptive capacity of stomach, whereas L-NAME treatment did not affect the stress-induced alterations on net fluid absorption. Furthermore, L-NAME treatment did not affect the cold restraint stress-induced changes in tissue MPO activity. Our results suggest that gastric barrier function is altered after cold-restraint stress and nitric oxide production is important in minimizing mucosal barrier dysfunction associated with cold-restraint stress administration. Our results also indicate that L-NAME-induced alterations on mucosal permeability are not related to net transmucosal fluid flux and tissue neutrophils.
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Affiliation(s)
- T Coskun
- Department of Physiology, Marmara University School of Medicine, Istanbul, Turkey
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9
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Takahashi A, Nagamachi Y, Hattori N. Effects of activated granulocytes and O2- on microcirculatory injury in acute gastric mucosal lesion in rats induced by sodium cinchophen. J Gastroenterol 1996; 31:153-60. [PMID: 8680532 DOI: 10.1007/bf02389511] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
The contribution of granulocytes and their byproducts to acute gastric mucosal lesion (AGML) is unclear. Our previous study showed that granulocytes produced O2- in the gastric mucosa of rats treated with 300 mg/kg of cinchophen (cinchophen ulcer, CU) and in rats subjected to 30 min-ischemia-reperfusion (IR). The present study investigated the effects of granulocytes and O2- on microcirculatory injury (MCI) in the gastric mucosa in both models. To evaluate MCI, we measured the amount of extravasated Evans blue, and monitored changes in blood flow and the formation of vascular casts in the gastric mucosa of rats with and without leukopenia. Mucosal levels of interleukin-8 (IL-8) were also measured, to determine granulocyte migration into the stomach. Our findings were: (1) IL-8 was decreased 30-45 min after CU injection (C-I) or after the start of occlusion (S-O), and levels had increased 90 min after either treatment. (2) Evans blue increased 120-150 min after C-I or S-O. These increases were lower in leukopenic than in non-leukopenic rats. (3) The blood flow decreased after C-I or reperfusion and continued at the same level during the 180-min measurement period. In CU leukopenic rats, the blood flow decreased slowly and was restored gradually. In IR leukopenic rats, the blood flow did not decrease. (4) There was a partial lack of capillary network, narrowing of capillaries, and extravasation of resin 90-120 min after C-I and S-O, and the disturbances were reduced in leukopenic rats in both models. (5) The extravasation of resin was reduced by the administration of superoxide dismutase (SOD) at the time O2- from granulocytes was being produced. (6) These reductions in the extravasation of resin due to leukopenia or SOD were smaller in CU than in IR rats. These findings indicate that granulocytes and O2- contribute to some extent to the MCI in CU rats.
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Affiliation(s)
- A Takahashi
- First Department of Surgery, Gunma University School of Medicine, Japan
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10
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Baquial JG, Sorenson JR. Down-regulation of NADPH-diaphorase (nitric oxide synthase) may account for the pharmacological activities of Cu(II)2 (3,5-diisopropylsalicylate)4. J Inorg Biochem 1995; 60:133-48. [PMID: 8530918 DOI: 10.1016/0162-0134(95)00008-c] [Citation(s) in RCA: 19] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Purposes of this work were to develop an enzyme system as an in vitro model of the NADPH-dependent component of nitric oxide synthase (NOS) and examine the plausible down-regulation of this system and brain NOS by copper (II)2(3,5-diisopropylsalicylate)4[Cu(II)2(3,5-DIPS)4] as a mechanism accounting for its analgesic, anticonvulsant, and other pharmacological activities. Porcine heart diaphorase (PHD) was found to oxidize 114 microM NADPH with the corresponding reduction of an equivalent amount of 2,6-dichlorophenolindophenol (DCPIP). Addition of Cu(II)2(3,5-DIPS)4 to the reaction mixture decreased the reduction of DCPIP without substantially affecting the oxidation of NADPH. The IC50 for Cu(II)2(3,5-DIPS)4 in inhibiting the reduction of DCPIP was 1.5 microM. Mechanistically, this inhibition of DCPIP reduction was found to be due to the ability of Cu(II)2(3,5-DIPS)4 to serve as a catalytic electron acceptor for reduced PHD, which was enhanced by the presence of a large concentration of DCPIP and inhibited by a large concentration of NADPH. Oxidation of NADPH by PHD in the absence of DCPIP was linearly related to the concentration of Cu(II)2(3,5-DIPS)4 through the concentration range of 5-25 microM Cu(II)2(3,5-DIPS)4 with 50% recovery of NADPH oxidation by PHD at a concentration of 16 microM Cu(II)2(3,5-DIPS)4. Whole rat brain tissue sections incubated in medium containing an NADPH-generating system and nitroblue tetrazolium chloride (NBT) were less intensely stained when Cu(II)2(3,5-DIPS)4 was added to the medium. It is concluded that Cu(II)2(3,5-DIPS)4 serves as an electron acceptor in down-regulating PHD reduction of DCPIP and in down-regulating NOS in brain tissue sections. A decrease in NO synthesis in animal models of seizure, pain, and other disease states with Cu(II)2(3,5-DIPS)4 may account for the anticonvulsant, analgesic, and other pharmacological activities of this complex.
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Affiliation(s)
- J G Baquial
- Department of Medicinal Chemistry, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock 72205, USA
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11
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Pfeiffer CJ, Qiu BS. Effects of chronic nitric oxide synthase inhibition on TNB-induced colitis in rats. J Pharm Pharmacol 1995; 47:827-32. [PMID: 8583351 DOI: 10.1111/j.2042-7158.1995.tb05749.x] [Citation(s) in RCA: 56] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Nitric oxide (NO) synthesis is increased in ulcerative colitis, but the role of NO in colitis is poorly understood. The present study employed Nw-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor, in rats to evaluate the effect of NO on 2,4,6-trinitrobenzenesulphonic acid (TNB)-induced colitis. L-NAME solutions were placed in subcutaneous, osmotic mini-pumps which continuously released L-NAME at 0.042, 0.208, 0.417, or 1.667 mg kg-1 h-1. L-NAME dose-dependently enhanced lesions in TNB-induced colitis. The two higher doses of L-NAME significantly increased colonic mucosal damage, although there was slight, nonsignificant reduced lesion formation with the lowest dose of L-NAME. 0.042 mg kg-1 h-1. A single dose of L-NAME at 100 mg kg-1 subcutaneously injected daily in TNB-treated rats also increased lesions, and these ulcerogenic actions of L-NAME were reversed by L-arginine but not by D-arginine (both at 500 mg kg-1, s.c.). Only the highest dose of L-NAME (mini-pump) significantly depressed myeloperoxidase (MPO) activity. Faecal occult bleeding showed a close relationship with severity of colitis. These findings suggest that there may exist a balance between NO protective and aggressive effects. In TNB-induced colitis, antagonism of endogenous NO generation was intensified, whereas slight inhibition of NO synthesis reduced lesions. Variations in responses, related to timing or dose changes in L-NAME, may reflect the differences in inducible vs constitutive NO synthase isoforms.
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Affiliation(s)
- C J Pfeiffer
- Department of Biomedical Sciences and Pathobiology, Virginia-Maryland Regional College of Veterinary Medicine, Virginia Tech, Blacksburg 24061-0442, USA
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Liu X, Nakano I, Yamaguchi H, Ito T, Goto M, Koyanagi S, Kinjoh M, Nawata H. Protective effect of nitric oxide on development of acute pancreatitis in rats. Dig Dis Sci 1995; 40:2162-9. [PMID: 7587783 DOI: 10.1007/bf02209000] [Citation(s) in RCA: 36] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
Nitric oxide (NO) has been implicated to regulate pancreatic circulation, promote capillary integrity, and inhibit leukocyte adhesion. We investigated the role of NO in the development of pancreatitis. Nitro-L-arginine, an inhibitor of NO synthase, in total dose of 35 mg/kg body wt was infused in the rats with edematous pancreatitis induced by two intraperitoneal injections of cerulein (20 micrograms/kg). L-Arginine (125 or 250 mg/kg), a NO donor was intravenously administered twice in the rats with hemorrhagic pancreatitis induced by water-immersion stress plus two intraperitoneal injections of cerulein (40 micrograms/kg). The degree of pancreas edema, serum amylase levels, and histologic alterations were investigated. Nitro-L-arginine exacerbated cerulein-induced pancreatitis and caused a decrease in pancreatic blood flow. L-Arginine ameliorated the severity of hemorrhagic pancreatitis dose dependently and improved the pancreatic blood flow. These findings suggest that NO could confer protection against the development of hemorrhagic pancreatitis, probably through improvement of the pancreatic microcirculation.
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Affiliation(s)
- X Liu
- Third Department of Internal Medicine, Faculty of Medicine, Kyushu University, Fukuoka City, Japan
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Tripp MA, Tepperman BL. Effect of nitric oxide on integrity, blood flow and cyclic GMP levels in the rat gastric mucosa: modulation by sialoadenectomy. Br J Pharmacol 1995; 115:344-8. [PMID: 7545520 PMCID: PMC1908316 DOI: 10.1111/j.1476-5381.1995.tb15883.x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023] Open
Abstract
1. The effects of the nitrosothiol, S-nitroso N-acetylpenicillamine (SNAP) which liberates nitric oxide (NO), on ethanol-mediated gastric damage, blood flow and cyclic GMP levels in siaoloadenectomized (SALX) rats have been investigated. 2. Intraluminal instillation of ethanol (5-50% w/v) dose-dependently induced haemorrhagic damage and decreased NO synthase activity in the gastric mucosa. Both the extent of mucosal damage and inhibition of NO synthase activity were exacerbated in SALX rats. 3. Epidermal growth factor administration (5 and 10 micrograms kg-1, s.c.) reduced mucosal damage but did not restore NO synthase activity in ethanol-treated SALX rats. 4. SNAP infusion (0.01-1.0 micrograms kg-1 min-1, i.v.) attenuated haemorrhagic damage in ethanol-treated rats. The reduction in mucosal damage was significantly greater in SALX rats. 5. SNAP administration also caused an increase in gastric mucosal blood flow and cyclic GMP levels in control rats and both responses were augmented in SALX animals. 6. These data suggest that SALX is associated with increases in mucosal susceptibility to ethanol-mediated damage and reduces mucosal NO synthase activity. Epidermal growth factor does not appear to influence mucosal NO synthase in ethanol-treated rats. Furthermore, SALX augments the responsiveness of the gastric mucosa to NO administration. Therefore, factors from the salivary glands influence gastric NO formation and mucosal responsiveness to a NO donor.
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Affiliation(s)
- M A Tripp
- Department of Physiology, Faculty of Medicine, University of Western Ontario, London, Canada
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14
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Wong D, Ogle CW. Chronic parenterally administered nicotine and stress- or ethanol-induced gastric mucosal damage in rats. Eur J Pharmacol 1995; 292:157-62. [PMID: 7720788 DOI: 10.1016/0926-6917(95)90008-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
Mini-osmotic pumps containing solutions of either 0.9% NaCl (infused at the rate of 0.5 microliter/h) or nicotine (infused in doses of 0.224, 1.03 or 1.88 mg/kg per day) were implanted s.c. into rats 12 days before experimentation. The alkaloid increased solid food consumption, but fluid intake and average weight gain were similar among the animals given saline or nicotine. Chronic nicotine treatment dose dependently intensified cold (4 degrees C)-restraint stress-induced ulceration and increased mast cell degranulation. Oral administration of 40% ethanol to nicotine-treated animals also produced greater mucosal damage; mast cell degranulation by ethanol was significantly worsened after alkaloid treatment. These findings show that the stress ulcer-intensifying action of the alkaloid is mainly through a systemic mechanism. In the case of ethanol-evoked mucosal damage, in addition to a topical effect, stimulation of the stomach wall ganglia is likely to participate in the exaggerated post-vagal ulcerogenic responses as seen in stress.
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Affiliation(s)
- D Wong
- Department of Pharmacology, Faculty of Medicine, University of Hong Kong
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15
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Lundberg JO, Weitzberg E, Lundberg JM, Alving K. Intragastric nitric oxide production in humans: measurements in expelled air. Gut 1994; 35:1543-6. [PMID: 7828969 PMCID: PMC1375608 DOI: 10.1136/gut.35.11.1543] [Citation(s) in RCA: 442] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
High values (800-6000 parts per billion) of nitric oxide (NO) in expelled air from the stomach were shown in humans by chemiluminescence technique. These NO values were more than 100 times higher than those found in orally exhaled air. Intragastric NO production is probably non-enzymatic, requiring an acidic environment, as NO in expelled air was reduced by 95% after pretreatment with the proton pump inhibitor omeprazole. Furthermore, large amounts of NO were formed in vitro from lettuce and saliva when placed in hydrogen chloride (pH < 2). In conclusion, large amounts of NO are formed intragastrically in humans and this source of NO may be of importance for the integrity of the gastric mucosa in health and disease. Measurements of NO in expelled air might be of value as a non-invasive method for estimation of gastric acidity.
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Affiliation(s)
- J O Lundberg
- Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden
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