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NEUROREGULATION AND MOTILITY

PAR-2 agonists induce contraction of murine small intestine through neurokinin receptors

Nutritional Requirements and Function Laboratory, Agricultural Research Service, United States Department of Agriculture, Beltsville 20705; and Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814-4799

Submitted 7 February 2003 ; accepted in final form 10 June 2003

Protease-activated receptor-2 (PAR-2) is a G protein-coupled receptor and is expressed throughout the gut. It is well known that PAR-2 participates in the regulation of gastrointestinal motility; however, the results are inconsistent. The present study investigated the effect and mechanism of PAR-2 activation on murine small intestinal smooth muscle function in vitro. Both trypsin and PAR-2-activating peptide SLIGRL induced a small relaxation followed by a concentration-dependent contraction. The sensitivity to trypsin was greater than that to SLIGRL (EC₅₀ = 0.03 vs. 40 µM), but maximal responses were similar (12.3 ± 1.6 vs. 13.7 ± 1.3 N/cm²). Trypsin-evoked contraction (1 µM) exhibited a rapid desensitization, whereas the desensitization of response to SLIGRL was less even at high concentration (50 µM). Atropine had no effect on PAR-2 agonist-induced contractions. In contrast, TTX and capsaicin significantly attenuated those contractions, implicating a neurogenic mechanism that may involve capsaicin-sensitive sensory nerves. Furthermore, contractions induced by trypsin and SLIGRL were reduced by neurokinin receptor NK₁ antagonist SR-140333 or NK₂ antagonist SR-48968 alone or were further reduced by combined application of SR-140333 and SR-48968, indicating the involvement of neurokinin receptors. In addition, desensitizing neurokinin receptors with substance P and/or neurokinin A decreased the PAR-2 agonist-evoked contraction. We concluded that PAR-2 agonists induced a contraction of murine intestinal smooth muscle that was mediated by nerves. The excitatory effect is also dependent on sensory neural pathways and requires both NK₁ and NK₂ receptors.

mouse; protease-activated receptor; trypsin

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