A protective role of protease-activated receptor 1 in rat gastric mucosa.
OBJECTIVE
On activation, protease-activated receptor (PAR)-2 modulates multiple gastric functions and exerts mucosal protection via activation of sensory neurons. The role of PAR-1, a thrombin receptor, in the stomach remains unknown. We thus examined if the PAR-1 agonist could protect against gastric mucosal injury in rats.


METHODS
Gastric mucosal injury was created by oral administration of ethanol/HCl or absolute ethanol in conscious rats. Gastric mucosal blood flow and acid secretion were determined in anesthetized rats. Immunohistochemical analyses of PAR-1 and cyclooxygenase (COX)-1 were also performed in rat and human stomach.


RESULTS
The PAR-1 agonist TFLLR-NH(2), administered intravenously in combination with amastatin, protected against the gastric mucosal injury induced by ethanol/HCl or absolute ethanol. The protective effect of TFLLR-NH(2) was abolished by indomethacin or a COX-1 inhibitor but not by ablation of sensory neurons with capsaicin. TFLLR-NH(2) produced an NO-independent increase in gastric mucosal blood flow that was partially inhibited by blockade of the endothelium-derived hyperpolarizing factor pathway. This inhibitory effect was promoted by indomethacin. TFLLR-NH(2) suppressed carbachol-evoked acid secretion in an indomethacin-reversible manner. Immunoreactive PAR-1 and COX-1 were expressed abundantly in rat gastric muscularis mucosae and smooth muscle, and the former protein was also detectable in blood vessels. Similar staining was observed in human gastric muscularis mucosae.


CONCLUSIONS
The PAR-1 agonist, given systemically, protects against gastric mucosal injury via COX-1-dependent formation of prostanoids, modulating multiple gastric functions. Our data identify a novel protective role for PAR-1 in gastric mucosa, and the underlying mechanism is entirely different from that for PAR-2.
Kawabata
Atsufumi
A
School of Pharmaceutical Sciences, Kinki University, Higashi-Osaka, Japan. kawabata@phar.kindai.ac.jp
Nishikawa
Hiroyuki
H
Saitoh
Hitomi
H
Nakaya
Yumiko
Y
Hiramatsu
Kaori
K
Kubo
Satoko
S
Nishida
Minoru
M
Kawao
Naoyuki
N
Kuroda
Ryotaro
R
Sekiguchi
Fumiko
F
Kinoshita
Mitsuhiro
M
Kakehi
Kazuaki
K
Arizono
Naoki
N
Yamagishi
Hisakazu
H
Kawai
Kenzo
K
D000818:Animals; D002217:Carbachol / Q000494:pharmacology; D051545:Cyclooxygenase 1; D019610:Cytoprotection; D000431:Ethanol; D005744:Gastric Acid / Q000378:metabolism; D005753:Gastric Mucosa / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D005769:Gastrointestinal Motility / Q000187:drug effects; D006801:Humans; D006851:Hydrochloric Acid; D007150:Immunohistochemistry; D007275:Injections, Intravenous; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins; D008875:Middle Aged; D009842:Oligopeptides / Q000008:administration & dosage / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D044463:Receptor, PAR-1 / Q000378:metabolism / Q000502:physiology*; D013270:Stomach / Q000187:drug effects / Q000473:pathology; D013272:Stomach Diseases / Q000139:chemically induced / Q000473:pathology; D014018:Tissue Distribution
D007527:Isoenzymes; D008565:Membrane Proteins; D009842:Oligopeptides; C462999:PAR-1-activating peptide; D044463:Receptor, PAR-1; D000431:Ethanol; D002217:Carbachol; D051545:Cyclooxygenase 1; C496511:PTGS1 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; C496513:Ptgs1 protein, rat; D006851:Hydrochloric Acid