The present study examined effects of agonist enzymes and receptor‐activating peptides for protease‐activated receptors (PARs) on duodenal motility in the rat, and also investigated possible mechanisms underlying the evoked responses.

Thrombin at 0.03–0.1 μM and the PAR‐1‐activating peptide SFLLR‐NH₂ at 3–100 μM or TFLLR‐NH₂ at 10–50 μM produced a dual action, relaxation followed by contraction of the duodenal longitudinal muscle. The PAR‐2‐activating peptide SLIGRL‐NH₂ at 10–100 μM elicited only small contraction. Trypsin at 0.08 μM induced small contraction, or relaxation followed by contraction, depending on preparations. The PAR‐4‐activating peptide GYPGKF‐NH₂ at 1000 μM exhibited no effect.

The contractile responses of the duodenal strips to TFLLR‐NH₂ and to SLIGRL‐NH₂ were partially attenuated by the L‐type calcium channel blocker nifedipine (1 μM), the protein kinase C inhibitor GF109203X (1 μM) and the tyrosine kinase inhibitor genistein (15 μM), but were resistant to indomethacin (3 μM) and tetrodotoxin (1–10 μM).

The relaxation of the preparations exerted by TFLLR‐NH₂ was unaffected by indomethacin (3 μM), propranolol (5 μM), N^G‐nitro‐L‐arginine methyl ester (100 μM) and tetrodotoxin (1–10 μM). This relaxation was resistant to either GF109203X (1 μM) or genistein (15 μM), but was, remarkably, attenuated by combined application of these two kinase inhibitors.

Apamin (0.1 μM), an inhibitor of calcium‐activated, small‐conductance potassium channels, but not charybdotoxin (0.1 μM), completely abolished the PAR‐1‐mediated duodenal relaxation, and significantly enhanced the PAR‐1‐mediated contraction.

These findings demonstrate that PAR‐1 plays a dual role, suppression and facilitation of smooth muscle motility in the rat duodenum, while PAR‐2 plays a minor excitatory role in the muscle, and that PAR‐4 is not involved in the duodenal tension modulation. The results also suggest that the contractile responses to PAR‐1 and PAR‐2 activation are mediated, in part, by activation of L‐type calcium channels, protein kinase C and tyrosine kinase, and that the relaxation response to PAR‐1 activation occurs via activation of apamin‐sensitive, but charybdotoxin‐insensitive, potassium channels, in which both protein kinase C and tyrosine kinase might be involved synergistically.