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GASTROPROTECTION: THE ROLE OF NITRIC OXIDE
OWONIKOKO, W. MATHEW
PHYSIOLOGY DEPARTMENT,
IGBINEDION UNIVERSITYOKADA, EDO STATE.
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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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
GASTRIC MUCOSA ENVIRONMENTGASTRIC MUCOSA ENVIRONMENT
Laine et al, 2008 4
BICARBONATE-RICH MUCOUS FROM SURFACE EPITHELIAL CELLBICARBONATE-RICH MUCOUS FROM SURFACE EPITHELIAL CELL
Silva and Sousa, 2011 5
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
HelicobacterHelicobacter pyloripylori AND ULCER AND ULCER FORMATIONFORMATION
Silva and Sousa, 2011 8
MECHANISM OF NSAIDs-INDUCED DAMAGEMECHANISM OF NSAIDs-INDUCED DAMAGE
Wallace, 2008. 9
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
REACTION AND CATALYSIS OF NOSREACTION AND CATALYSIS OF NOS
Alderton et al, 2001 12
TYPES OF NOSTYPES OF NOS
Alderton et al, 2001 13
NITRIC OXIDE IN THE ACT NITRIC OXIDE IN THE ACT
14Wallace and Miller, 2000.
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
ACTIONS OF NO ACTIONS OF NO
Kolios et al, 2004 16
NO IN MUCOSA BLOODFLOWNO IN MUCOSA BLOODFLOW
Kolluru et al, 2012 17
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
ULCER HEALING PROCESSESULCER HEALING PROCESSES
Fornai et al, 2011 20
NITRIC OXIDE AND WOUND NITRIC OXIDE AND WOUND HEALINGHEALING
Luo and Chen, 2005 21
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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