PT  - JOURNAL ARTICLE
AU  - Hiroyuki Nishikawa
AU  - Kenzo Kawai
AU  - Makoto Tanaka
AU  - Hiroya Ohtani
AU  - Shuichi Tanaka
AU  - Chizuko Kitagawa
AU  - Minoru Nishida
AU  - Tomoyuki Abe
AU  - Hiromasa Araki
AU  - Atusufumi Kawabata
TI  - Protease-Activated Receptor-2 (PAR-2)-Related Peptides Induce Tear Secretion in Rats: Involvement of PAR-2 and Non-PAR-2 Mechanisms
AID  - 10.1124/jpet.104.072074
DP  - 2005 Jan 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 324--331
VI  - 312
IP  - 1
4099  - http://jpet.aspetjournals.org/content/312/1/324.short
4100  - http://jpet.aspetjournals.org/content/312/1/324.full
SO  - J Pharmacol Exp Ther2005 Jan 01; 312
AB  - Protease-activated receptor-2 (PAR-2) plays an extensive role in the regulation of digestive exocrine secretion. The present study examined whether PAR-2-related peptides could modulate tear secretion in rats and analyzed the underlying mechanisms. SLIGRL-NH2, a PAR-2-activating peptide (PAR-2-AP) derived from mouse/rat PAR-2, when administered i.v. in combination with amastatin, an aminopeptidase inhibitor, evoked tear secretion, whereas LRGILS-NH2, a PAR-2-inactive reversed peptide, had no such effect. In contrast, LSIGRL-NH2, a partially reversed peptide known to be inactive with PAR-2, caused tear secretion equivalent to the effect of SLIGRL-NH2. SLIGKV-NH2, a human-derived PAR-2-AP, also induced significant tear secretion though to a lesser extent, whereas neither VKGILS-NH2, a reversed peptide, nor LSIGKV-NH2, a partially reversed peptide, produced any secretion. In desensitization experiments, after the first dose of SLIGRL-NH2, the second dose of SLIGRL-NH2 produced no tear secretion, whereas the response to LSIGRL-NH2 was only partially inhibited by preadministration of SLIGRL-NH2. Preadministration of LSIGRL-NH2 abolished the response to subsequently administered LSIGRL-NH2 but not SLIGRL-NH2. The tear secretion induced by LSIGRL-NH2 but not by PAR-2-APs was blocked by atropine or hexamethonium. Mast cell depletion due to repeated doses of compound 48/80 did not alter the effect of SLIGRL-NH2 or LSIGRL-NH2. Finally, IGRL-NH2, a possible core structure of LSIGRL-NH2, triggered tear secretion in an atropine-reversible manner. Our findings suggest that the PAR-2-APs SLIGRL-NH2 and SLIGKV-NH2 cause tear secretion, most likely via PAR-2 and that LSIGRL-NH2, a PAR-2-inactive peptide, and IGRL-NH2, its key structure, trigger tear secretion by stimulating parasympathetic nerves via an unidentified target molecule. The American Society for Pharmacology and Experimental Therapeutics