Protease-activated receptors mediate apamin-sensitive relaxation of mouse and guinea pig gastrointestinal smooth muscle.
OBJECTIVE
Protease-activated receptor (PAR)-1 and PAR-2 are expressed on gastrointestinal smooth muscle, but knowledge of their functionality is limited. The aim of this study was to determine if PAR-1 and PAR-2 mediate gastrointestinal smooth muscle relaxation and to clarify the underlying mechanisms.


METHODS
Responses to PAR activation using the serine proteases thrombin and trypsin and the peptide agonists for PAR-1 and PAR-2, SFLLRN-NH2 and SLIGRL-NH2, respectively, were investigated in submaximally contracted longitudinal strips of mouse gastric fundus and guinea pig taenia coli.


RESULTS
In mouse gastric fundus, both thrombin and trypsin caused relaxations followed by contractions. SFLLRN-NH2 and SLIGRL-NH2 caused similar biphasic responses, the relaxation components of which were eliminated by apamin or ryanodine. For SFLLRN-NH2, apamin and ryanodine revealed contractions. Nifedipine inhibited both relaxations and contractions to each peptide. In guinea-pig taenia coli, thrombin but not trypsin caused relaxation, whereas SFLLRN-NH2 and SLIGRL-NH2 caused concentration-dependent relaxations that were eliminated by apamin but were unaffected by ryanodine.


CONCLUSIONS
The mouse gastric fundus and guinea pig taenia coli contain functional PAR-1 and PAR-2 that mediate relaxations via ryanodine-sensitive and -insensitive activation of small-conductance, Ca2+-activated K+ channels. We propose that smooth muscle PARs act as sensors for inflammatory signals in gut and respond by inhibiting gut motility during peritoneal infections or tissue damage.
Department of Pharmacology, University of Melbourne, Parkville, Victoria, Australia. t.cocks@pharmacology.unimelb.edu.au
T M
TM
Cocks
V
V
Sozzi
J D
JD
Moffatt
S
S
Selemidis
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001030:Apamin / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D003106:Colon / Q000187:drug effects / Q000502:physiology*; D005748:Gastric Fundus; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009126:Muscle Relaxation / Q000187:drug effects / Q000502:physiology*; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology*; D019335:Nitroarginine / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D044463:Receptor, PAR-1; D044464:Receptor, PAR-2; D018179:Receptors, Thrombin / Q000187:drug effects / Q000502:physiology*; D013270:Stomach / Q000187:drug effects / Q000502:physiology*; D013779:Tetrodotoxin / Q000494:pharmacology; D013917:Thrombin / Q000494:pharmacology
D002121:Calcium Channel Blockers; D009842:Oligopeptides; D010446:Peptide Fragments; D044463:Receptor, PAR-1; D044464:Receptor, PAR-2; D018179:Receptors, Thrombin; C112356:seryl-leucyl-isoleucyl-glycyl--arginyl-leucinamide; C082835:thrombin receptor peptide (42-47); D019335:Nitroarginine; D001030:Apamin; D013779:Tetrodotoxin; D013917:Thrombin; D000109:Acetylcholine