The protease-activated receptor-2 agonist induces gastric mucus secretion and mucosal cytoprotection

Protease-activated receptor-2 (PAR-2), a receptor activated by trypsin/tryp tase, modulates smooth muscle tone and exocrine secretion in the salivary g lands and pancreas. Given that PAR-2 is expressed throughout the gastrointe stinal tract, rye investigated effects of PAR-2 agonists on mucus secretion and gastric mucosal injury in the rat. PAR-2-activating peptides triggered secretion of mucus in the stomach, but not in the duodenum. This mucus sec retion was abolished by pretreatment with capsaicin, which stimulates and a blates specific sensory neurons, but: it was resistant to cyclo-oxygenase i nhibition. In contrast, capsaicin treatment failed to block PAR-2-mediated secretion from the salivary glands. Intravenous calcitonin gene-related pep tide (CGRP) and neurokinin A markedly elicited gastric mucus secretion, as did substance P to a lesser extent. Specific antagonists of the CGRP(1) and NK2, but not the NK1, receptors inhibited PAR-2-mediated mucus secretion. Pretreatment with the PAR-2 agonist strongly prevented gastric injury cause d by HCl-ethanol or indomethacin. Thus, PAR-2 activation triggers the cytop rotective secretion of gastric mucus by stimulating the release of CGRP and tachykinins from sensory neurons. In contrast, the PAR-2-mediated salivary exocrine secretion appears to be independent of capsaicin-sensitive sensor y neurons.