Abstract
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 [6.25–100 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 (PGI2) 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/PGI2 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)-1H-pyrazole; SC-560] and COX-2 [4-(4-methylsulfonylphenyl)-3-phenyl-5H-furan-2-one; rofecoxib] activity, capsaicin denervation, and by the pretreatment with CGRP8-37 or capsazepine. Addition of exogenous PGI2 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 PGI2 and CGRP in preservation of microvascular flow, antioxidizing enzyme SOD activity, and reduction in lipid peroxidation.
Footnotes
-
This work was supported by Grant PBZ-KBN-101/T09/2003 from the Polish Ministry of Science and Higher Education.
-
The article contains the data from Kwiecién S, Brzozowski T, Konturek PC, Sliwowski Z, Chlopicki S, Slonimska E, Gebicki J, Konturek SJ, and Pawlick WW (2007) Role of prostaglandin (PG), nitric oxide (NO) and lipid peroxidation in the gastroprotective and ulcer healing activities of 1-methylnicotinamide (MNA). Gastroenterology132 (Suppl. 2): A411–A412.
-
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
-
doi:10.1124/jpet.108.136457.
-
ABBREVIATIONS: NA, nicotinamide; MNA, 1-methylnicotinamide; M2PY, 1-methyl-2-pyridone-5-carboxamide; M4PY, 1-methyl-1–4-pyridone-5-carboximide; PGI2, prostacyclin; PGE2, prostaglandin E2; COX, cyclooxygenase; RO 3244794, R-3-(4-fluoro-phenyl)-2-[5-(4-fluoro-phenyl)-benzofuran-2-ylmethoxycarbonylamino]-propionic acid; CGRP, calcitonin gene-related peptide; WRS, water immersion and restraint stress; GBF, gastric blood flow; SOD, superoxide dismutase; MDA, malonyldialdehyde; GF, gastric fistula; SC-560, 5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole; i.g., intragastrically; TRPV1, transient receptor potential vanilloid type 1; RT-PCR, reverse transcriptase-polymerase chain reaction; 4-HNE, PG, prostaglandin; 4-HNE, trans-4-hydroxy-2-nonenal.
- Received January 16, 2008.
- Accepted April 1, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|