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GASTROPROTECTION: THE ROLE OF NITRIC OXIDE OWONIKOKO, W. MATHEW PHYSIOLOGY DEPARTMENT, IGBINEDION UNIVERSITY OKADA, EDO STATE. ([email protected]) 1
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gastroprotective role of nitric oxide

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Page 1: gastroprotective role of nitric oxide

GASTROPROTECTION: THE ROLE OF NITRIC OXIDE

OWONIKOKO, W. MATHEW

PHYSIOLOGY DEPARTMENT,

IGBINEDION UNIVERSITYOKADA, EDO STATE.

([email protected]) 1

Page 2: gastroprotective role of nitric oxide

OUTLINEOUTLINEThe functional anatomy of the stomachGastric defence mechanismsMechanisms of gastropathyGastric physiological conditionGastric pathological conditionNitric Oxide (NO)NO in physiological gastroprotectionNO in healing processesConclusion

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Page 3: gastroprotective role of nitric oxide

THE STOMACHTHE STOMACHLocated in the upper left quadrant of the abdominal cavity to the left of the liver and in front of the spleen, the stomach has the following functions, namely;StorageDigestionMix the stomach’s contentInhibit bacterial growthProvide intrinsic factor for Vitamin B12 absorptionRegulate the rate of emptying to the small intestineConstant exposure of the stomach to detrimental agents in foods and other substances predisposes the stomach to gastropathies.

William, 2009 3

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GASTRIC MUCOSA ENVIRONMENTGASTRIC MUCOSA ENVIRONMENT

Laine et al, 2008 4

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BICARBONATE-RICH MUCOUS FROM SURFACE EPITHELIAL CELLBICARBONATE-RICH MUCOUS FROM SURFACE EPITHELIAL CELL

Silva and Sousa, 2011 5

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GASTROPATHYGASTROPATHY• Gastropathies e.g. peptic ulcer is a deep

defect in the gastric wall penetrating the entire mucosal thickness and the muscularis mucosa (Tarnawski, 2000).

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STOMACH IN HEALTH AND STOMACH IN HEALTH AND DISEASEDISEASE

Silva and Sousa, 2011 7

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HelicobacterHelicobacter pyloripylori AND ULCER AND ULCER FORMATIONFORMATION

Silva and Sousa, 2011 8

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MECHANISM OF NSAIDs-INDUCED DAMAGEMECHANISM OF NSAIDs-INDUCED DAMAGE

Wallace, 2008. 9

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NITRIC OXIDENITRIC OXIDEFirst gas known to act as a biological messenger; it serves different

functions depending on body system. i.e. neurotransmitter, vasodilator, bactericide.

Nitric oxide is a diatomic free radical consisting of one atom of nitrogen and one atom of oxygen.

Its one of the smallest molecules in nature and the natural form is a gas

NO can be transported to the target cell due to its following features It is small, lipid-soluble, uncharged and the half life is less than

30sec in living systems, hence capable of diffusing through the cellmembrane

It interact with thiol groups forming Nitrosothiols (SNO) (Nitin et al, 2011).

N O

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SOURCES OF NITRIC OXIDESOURCES OF NITRIC OXIDE1. NO can be produced from L-arginine by NOS (Nitin et al, 2011)

2. Also dietary nitrate is reduced in the oral cavity to nitrite by bacterial reductase (Duncan et al, 1995) yielding NO after acidification in gastric lumen (McKnight et al, 1997)

3. NO can as well be produced from nitrite and nitrate during hypoxic condition by Xanthine oxidoreductase enzyme.

4. H2O2 react with arginine producing NO (Nagase et al, 1997)

5. NO is produced in the colon by anaerobic bacteria (Brittain et al, 1992).

1,2 and 3 above are enzyme dependent while 3 and 4 are non-enzyme dependent.

COO-

C

(CH2)3

NH

C

H2N

H

NH2+

+H3N

Arginine

NOS

NADPH

+ O2

NAD+

COO-

C

(CH2)3

NH

C

H+H3N

N+

H2NH

OH

N-w-Hydroxyarginine

COO-

C

(CH2)3

NH

H+H3N + NO

NOS

C

O NH2

Citrulline11

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REACTION AND CATALYSIS OF NOSREACTION AND CATALYSIS OF NOS

Alderton et al, 2001 12

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TYPES OF NOSTYPES OF NOS

Alderton et al, 2001 13

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NITRIC OXIDE IN THE ACT NITRIC OXIDE IN THE ACT

14Wallace and Miller, 2000.

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TARGETS FOR THE GASTROPROTECTIVE ROLE OF NO ON NSAID-TARGETS FOR THE GASTROPROTECTIVE ROLE OF NO ON NSAID-INDUCED GASTRIC DAMAGEINDUCED GASTRIC DAMAGE

Mannick et al,1996. 15

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ACTIONS OF NO ACTIONS OF NO

Kolios et al, 2004 16

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NO IN MUCOSA BLOODFLOWNO IN MUCOSA BLOODFLOW

Kolluru et al, 2012 17

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ULCER HEALING“CONDIMENTS”ULCER HEALING“CONDIMENTS”Gastric Ulcer healing is an active and complicated

process: • Inflammation, granulation tissue formation, • Tissue remodeling, Angiogenesis, • Cell division, • Fibroblast migration, • Mucosal regeneration,• Reconstruction of gastric glands, etc. (Tarnawski,

2000).Processes controlled by factors: • TNF-alpha, COX-2, PGE2, • Serum Response Factor (SRF), • Nitric Oxide (NO), Angiopoietins,• Endothelin, Metalloproteinases, • Transcription factors, Cytokines, etc. (Schmassmann,

2005).

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MOLECULAR UPREGULATIONS IN WOUND HEALING PROCESSES MOLECULAR UPREGULATIONS IN WOUND HEALING PROCESSES

Gould et al, 2008 19

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ULCER HEALING PROCESSESULCER HEALING PROCESSES

Fornai et al, 2011 20

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NITRIC OXIDE AND WOUND NITRIC OXIDE AND WOUND HEALINGHEALING

Luo and Chen, 2005 21

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RECOMMENDATION AND CONCLUSIONRECOMMENDATION AND CONCLUSIONNSAIDs and H. pylori are capable of enormous erosion of gastro-protective agents and should best be avoided.

The mechanism of NO protection in normal gastric conditions include mucus, acid, bicarbonate and prostaglandins secretion, while re-epithelialization, tissue remodelling, angiogenesis etc which are the major processes involved in gastric injury healing remains the same target for NO gastro-protections.

Hence, clinical development of NO-NSAIDs has newly been introduced but still has to be completed before its potentials in human can be fully validated; even though the available pre-clinical and clinical data are encouraging.

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REFERENCESREFERENCES Laine L., et al. (2008). Gastric mucosal defense and cytoprotection: bench

to bedside. Gastroenterology, Vol.135, No.1, (July 2008), pp.41-60 Tarnawski, 2000 Schmassmann, 2005 Kolluru et al, 2012.Endothelial Dysfunction and Diabetes: Effects on

Angiogenesis, Vascular Remodeling, andWound Healing, International Journal of Vascular Medicine

Wallace, 2009. Cyclooxygenase-inhibiting nitric oxide donators for osteoarthritis; Trends in Pharmacological Sciences Vol.30 No.3

Luo and Chen, 2005. Nitric oxide: a newly discovered function on wound healing. Acta pharmacologica sinica; 26 (3), pg 259-264.

Nitin et al, 2011. Nitric oxide and the gastrointestinal tract. International journal of pharmacology; 7 (1) pg 31-39.

Wallace JL, Miller MJS, 2000: Nitric oxide in mucosal defence. A little goes a long way. Gastroenterology, vol. 119 pg 512-520

Duncan et al, 1995. chemical generation of nitric oxide in the mouth from the enterosalivary circulation of dietary nitrate. Nat. Med., 1: 546-551

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REFERENCESREFERENCES McKnight et al, 1997. chemical synthesis of nitric oxide in the stomach

from dietary nitrate in humans. Gut, 40: 211-214. Nagase et al, 1997. A novel nonenzymatic pathway for the generation of

nitric oxide by the reaction of hydrogen peroxide and D- or L-arginine. Biochem. Biophys. Res. Commun., 233: 150-153.

Brittain et al, 1992. Bacterial nitrite-reducing enzymes. Eur. J. biochem., 209: 793-802

Gould et al, 2008. Arginine metabolism and wound healing Wound. Healing Southern Africa;1(1):48-50.

Alderton et al, 2001. Nitric oxide synthases : structure, function and inhibition. Biochem. J. 357, 593±615

Kolios et al, 2004. Nitric oxide in inflammatory bowel disease: a universal messenger in an unsolved puzzle. Immunology vol 113 427–437

Matteo Fornai, Luca Antonioli, Rocchina Colucci, Marco Tuccori and Corrado Blandizzi (2011). Pathophysiology of Gastric Ulcer Development and Healing: Molecular Mechanisms and Novel Therapeutic Options, Peptic Ulcer Disease, Dr. Jianyuan Chai (Ed.), ISBN: 978-953-307-976-9 24

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..

I

APPRECIATE

YOUR

ATTENTION!!!

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