Protease-activated receptors mediate apamin-sensitive relaxation of mouse and guinea pig gastrointestinal smooth muscle

Background & Aims: Protease-activated receptor (PAR)-1. and PAR-2 are expre ssed on gastrointestinal smooth muscle, but knowledge of their functionalit y is limited. The aim of this study was to determine if PAR-1 and PAR-2 med iate gastrointestinal smooth muscle relaxation and to clarify the underlyin g mechanisms, Methods: Responses to PAR activation using the serine proteas es thrombin and trypsin and the peptide agonists for PAR-1 and PAR-2, SFLLR N-NH2 and SLIGRL-NH2, respectively, were investigated in submaximally contr acted longitudinal strips of mouse gastric fundus and guinea pig taenia col i. Results: in mouse gastric fundus, both thrombin and trypsin caused relax ations followed by contractions, SFLLRN-NH2 and SLIGRL-NH2 caused similar b iphasic responses, the relaxation components of which were eliminated by ap amin or ryanodine. For SFLLRN-NH2, apamin and ryanodine revealed contractio ns. Nifedipine inhibited both relaxations and contractions to each peptide. in guinea-pig taenia coli, thrombin but not trypsin caused relaxation, whe reas SFLLRN-NH2 and SLIGRL-NH2 caused concentration-dependent relaxations t hat were eliminated by apamin hut were unaffected by ryanodine. Conclusions : The mouse gastric fundus and guinea pig taenia coil contain functional PA R-1 and PAR-2 that mediate relaxations via ryanodine-sensitive and -insensi tive activation of small-conductance, Ca2+-activated K+ channels. We propos e that smooth muscle PARs act as sensors for Inflammatory signals in gut an d respond by inhibiting gut motility during peritoneal infections or tissue damage.