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Therapeutic Potential of 1-Methylnicotinamide against Acute Gastric Lesions Induced by Stress: Role of Endogenous Prostacyclin and Sensory Nerves
1-Methylnicotinamide (MNA) is one of the major derivatives of nicotinamide, which was recently shown to exhibit antithrombotic and antiinflammatory actions. However, it is not yet known whether MNA affects gastric mucosal defense. The effects of exogenous MNA were studied on gastric secretion and ga...
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Published in: | The Journal of pharmacology and experimental therapeutics 2008-07, Vol.326 (1), p.105-116 |
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Main Authors: | , , , , , , , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
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Online Access: | Get full text |
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Summary: | 1-Methylnicotinamide (MNA) is one of the major derivatives of nicotinamide, which was recently shown to exhibit antithrombotic
and antiinflammatory actions. However, it is not yet known whether MNA affects gastric mucosal defense. The effects of exogenous
MNA were studied on gastric secretion and gastric lesions induced in rats by 3.5 h of water immersion and water restraint
stress (WRS) or in rats administered 75% ethanol. MNA [6.25â100 mg/kg intragastrically (i.g.)] led to a dose-dependent rise
in the plasma MNA level, inhibited gastric acid secretion, and attenuated these gastric lesions induced by WRS or ethanol.
The gastroprotective effect of MNA was accompanied by an increase in the gastric mucosal blood flow and plasma calcitonin
gene-related peptide (CGRP) levels, the preservation of prostacyclin (PGI 2 ) generation (measured as 6-keto-PGF1α), and an overexpression of mRNAs for cyclooxygenase (COX)-2 and CGRP in the gastric
mucosa. R -3-(4-Fluoro-phenyl)-2-[5-(4-fluoro-phenyl)-benzofuran-2-ylmethoxycarbonylamino]-propionic acid (RO 324479), which is the
selective antagonist of IP/PGI 2 receptors, reversed the effects of MNA on gastric lesions and GBF. MNA-induced gastroprotection was attenuated by suppression
of COX-1 [5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-(trifluoromethyl)-1 H -pyrazole; SC-560] and COX-2 [4-(4-methylsulfonylphenyl)-3-phenyl-5 H -furan-2-one; rofecoxib] activity, capsaicin denervation, and by the pretreatment with CGRP 8-37 or capsazepine. Addition of exogenous PGI 2 or CGRP restored the MNA-induced gastroprotection in rats treated with COX-1 and COX-2 inhibitors or in those with capsaicin
denervation. WRS enhanced MDA content while decreasing superoxide dismutase (SOD) activity in the gastric mucosa, but pretreatment
with MNA reversed these changes. MNA exerts potent gastroprotection against WRS damage via mechanisms involving cooperative
action of PGI 2 and CGRP in preservation of microvascular flow, antioxidizing enzyme SOD activity, and reduction in lipid peroxidation. |
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ISSN: | 0022-3565 1521-0103 |
DOI: | 10.1124/jpet.108.136457 |