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ABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Protease-Activated Receptor-2 (PAR-2)-Related Peptides Induce Tear Secretion in Rats: Involvement of PAR-2 and Non-PAR-2 Mechanisms

Research and Development Center (H.N., K.K., M.T., H.O., S.T., C.K., M.N., T.A., H.A.), Fuso Pharmaceutical Industries Ltd., Osaka, Japan; and Division of Physiology and Pathophysiology (A.K.), School of Pharmaceutical Sciences, Kinki University, Higashi-Osaka, Japan

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.

Address correspondence to: Dr. Atsufumi Kawabata, Division of Physiology and Pathophysiology, School of Pharmaceutical Sciences, Kinki University, 3-4-1 Kowakae, Higashi-Osaka 577-8502, Japan. E-mail: kawabata{at}phar.kindai.ac.jp