Gastroprotective effects of amtolmetin guacyl: a new non-steroidal anti-inflammatory drug that activates inducible gastric nitric oxide synthase.
BACKGROUND
The novel non-steroidal anti-inflammatory drug amtolmetin guacyl has been shown to possess markedly reduced ulcerogenic effects and nitric oxide-mediated gastroprotective activity against the damage induced by ethanol in the rat.


OBJECTIVE
To investigate, in the rat, the role of nitric oxide and of inducible nitric oxide synthase isoform in the protective effect of amtolmetin guacyl against the gastric damage induced by ethanol.


METHODS
The effects of amtolmetin guacyl on gastric transmucosal potential difference and on gastric mucosal blood flow were investigated in the anaesthetised rat; myeloperoxidase activity, inducible and endothelial nitric oxide synthase protein content were determined in rat gastric mucosal homogenates. The anti-inflammatory drug tolmetin and the bacterial lipopolysaccharide from Escherichia coli were studied for comparison.


RESULTS
In the anaesthetised rat, amtolmetin guacyl, but not tolmetin, reduced by approximately 50% the fall in gastric potential difference and, to a lesser extent, the macroscopic damage induced by ethanol. The effect of amtolmetin guacyl on transmucosal potential difference was prevented by the selective inducible nitric oxide synthase inhibitor 1400W. In amtolmetin guacyl-treated rats, 1400W decreased gastric mucosal blood flow, whereas it was inactive in vehicle- and tolmetin-treated animals. In gastric mucosal homogenates, both amtolmetin guacyl and lipopolysaccharide, but not tolmetin, increased inducible, but not endothelial, nitric oxide synthase protein content, as revealed by Western immunoblotting.


CONCLUSIONS
These data confirm that amtolmetin guacyl is a non-steroidal anti-inflammatory agent devoid of gastrolesive properties, that can actually reduce the damaging effects of ethanol through the increase in nitric oxide production, via the inducible isoform of nitric oxide synthase.
Coruzzi
G
G
Institute of Pharmacology, School of Medicine, University of Parma, Italy. gabriella.coruzzi@unipr.it
Coppelli
G
G
Spaggiari
S
S
Cavestro
G M
GM
Okolicsanyi
L
L
Lo Giudice
P
P
Pisano
C
C
Tepperman
B L
BL
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D000431:Ethanol / Q000009:adverse effects; D005753:Gastric Mucosa / Q000187:drug effects*; D005998:Glycine / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D008070:Lipopolysaccharides / Q000627:therapeutic use; D008297:Male; D009569:Nitric Oxide / Q000096:biosynthesis; D019001:Nitric Oxide Synthase / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D011758:Pyrroles / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D014046:Tolmetin / Q000627:therapeutic use
D000894:Anti-Inflammatory Agents, Non-Steroidal; D008070:Lipopolysaccharides; D011758:Pyrroles; C065762:ST 679; D009569:Nitric Oxide; D000431:Ethanol; D014046:Tolmetin; D009195:Peroxidase; D019001:Nitric Oxide Synthase; D005998:Glycine