The induction of carbon monoxide-mediated airway relaxation by PACAP 38 in isolated guinea pig airways

Pituitary adenylate cyclase-activating! peptide 38 (PACAP 38) displays several biologic activities relevant to obstructive airway disease. Carbon monoxide (CO) has recently emerged as a potent, endogenously produced mediator of bronchodilation. In this study, we have analyzed the occurrence of PACAP 38 and the corresponding occurrence of heme oxygenase (MO), the rate-limiting enzyme for CO production, in guinea pig trachea, using immunocytochemistry. We have also investigated whether the dilatory effects of PACAP 38 are dependent on CO, using an in vitro setup for tracheal studies. A moderate supply of PACAP-like immunoreactive nerve fibers was seen in association with tracheal smooth muscle. MO-like immunoreactivity was observed in the respiratory epithelium and in association with smooth muscle bundles. PACAP 38 induced a concentration-dependent relaxation of precontracted tracheal segments. This: dilation aias nearly abolished after pre treatment with zincprotoporphyrine, an inhibitor of heme oxygenase. The same effect was accomplished with Rp-8Br-cyclicGMPS, an inhibitor of cyclicGMP, whereas the nitric oxide synthase inhibitor NG-monomethyl-L-arginine had no effect on the PACAP 38-induced dilation. The presented data suggest that PACAP 38 can induce bronchodilation by means of a CO-dependent, cycliicGMP-related mechanism, thereby providing a link between neurotransmission and local CO release in the airway smooth muscle.