Presence and bronchomotor activity of protease-activated receptor-2 in guinea pig airways

The protease activated receptor-2 (PAR-2) belongs to a family of G-protein- coupled receptors that are activated by proteolysis. Trypsin cleaves PAR-2 exposing an N-terminal tethered ligand (SLIGRL) that activates the receptor . Messenger RNA (mRNA) for PAR-2 was found in guinea pig airway tissue by r everse transcription-polymerase chain reaction, and PAR-2 was found by immu nohistochemistry in airway epithelial and smooth-muscle cells. In anestheti zed guinea pigs, trypsin and SLIGRL-NH2 (given intratracheally or intraveno usly) caused a bronchoconstriction that was inhibited by the combination of tachykinin-NK1 and -NK2 receptor antagonists and was potentiated by inhibi tion of nitric oxide synthase (NOS). Trypsin and SLIGRL-NH2 relaxed isolate d trachea and main bronchi, and contracted intrapulmonary bronchi. Relaxati on of main bronchi was abolished or reversed to contraction by removal of e pithelium, administration of indomethacin, and NOS inhibition. PAR-1, PAR-3 , and PAR-4 were not involved in the bronchomotor action of either trypsin or SLIGRL-NH2, because ligands of these receptors were inactive either in v itro or in vivo, and because thrombin (a PAR-1 and PAR-3 agonist) did not s how cross-desensitization with PAR-2 agonists in vivo. Thus, we have locali zed PAR-2 to the guinea-pig airways, and have shown that activation of PAR- 2 causes multiple motor effects in these airways, including in vivo broncho constriction, which is In part mediated by a neural mechanism.