Involvement of nitric oxide and tachykinins in the effects induced by protease‐activated receptors in rat colon longitudinal muscle

The aim of the present study was to verify a possible involvement of nitric oxide (NO) and of tachykinins in the contractile and relaxant effects caused by the activation of protease‐activated receptor (PAR)‐1 and PAR‐2 in the longitudinal muscle of rat colon. Mechanical responses to the PAR‐1 activating peptides, SFLLRN‐NH 2 (10 n M –10 μ M ) and TFLLR‐NH 2 (10 n M –10 μ M ), and to the PAR‐2‐activating peptide, SLIGRL‐NH 2 (10 n M –10 μ M ), were examined in vitro in the absence and in the presence of different antagonists. The relaxation induced by SFLLRN‐NH 2 , TFLLR‐NH 2 and SLIGRL‐NH 2 was antagonised by the inhibitor of NO synthase L ‐ N ω ‐nitroarginine methyl ester (300 μ M ), or by the inhibitor of the guanylyl cyclase, 1‐H‐oxodiazol‐[1,2,4]‐[4,3‐a]quinoxaline‐1‐one (10 μ M ). The contractile responses to PAR‐1 and PAR‐2 activation were concentration‐dependently attenuated by SR140333 (0.1–1 μ M ), NK 1 receptor antagonist, or by SR48968 (0.1–1 μ M ), NK 2 receptor antagonist. The combined pretreatment with SR140333 (1 μ M ) and SR48968 (1 μ M ) produced additive suppressive effects on the contractile responses to PAR activation. Pretreatment of the preparation with capsaicin (10 μ M ) markedly reduced the contractions evoked by SFLLRN‐NH 2 , TFLLR‐NH 2 and SLIGRL‐NH 2 , while ω ‐conotoxin GVIA (0.2 μ M ) had no effect. The present results suggest that in rat colonic longitudinal muscle, PAR‐1 and PAR‐2 activation can evoke (i) relaxation through the production of NO or (ii) contraction through the release of tachykinins, likely, from sensory nerves. These actions may contribute to motility disturbances during intestinal trauma and inflammation.British Journal of Pharmacology (2003) 139 , 598–604. doi: 10.1038/sj.bjp.0705273