Effects of peptidases on non‐adrenergic, non‐cholinergic inhibitory responses of tracheal smooth muscle: a comparison with effects on VIP‐ and PHI‐induced relaxation

Abstract

1 The effects of peptidase enzymes on non-adrenergic, non-cholinergic (NANC) inhibitory responses of guinea-pig trachea to electrical field stimulation (EFS), and on relaxations induced by vasoactive intestinal peptide (VIP) and peptide histidine isoleucine (PHI) have been examined. 2 a-Chymotrypsin reduced both the magnitude and, particularly, the duration of the inhibitory response to EFS, whereas papain reduced only the magnitude. Aprotinin, a peptidase inhibitor prevented the effects of a-chymotrypsin but was without effect on papain. 3 a-Chymotrypsin and papain both abolished relaxant responses to exogenous VIP and PHI. The action of a-chymotrypsin was prevented by aprotinin, whereas that of papain was not affected. 4 The peptidases were without effect on concentration-response curves to methacholine or to isoprenaline. It was also observed that, in the absence of the peptidases, aprotinin had no effect on inhibitory responses either to EFS or to exogenous VIP and PHI. 5 It is suggested that neuropeptides, possibly VIP and PHI, released during EFS of guinea-pig trachea, partly mediate NANC relaxations, and that their action may be inhibited by peptidases. However, the lack of effect of aprotonin alone, on responses to EFS, suggests that, if endogenous peptidases are important in terminating the action of neuropeptides, they are resistant to the effect of this particular peptidase inhibitor. It is further suggested that neurogenic relaxation of guinea-pig trachea is also partly mediated by a substance, possibly non-peptide, other than VIP or PHI.

Evidence that part of the NANC relaxant response of guinea‐pig trachea to electrical field stimulation is mediated by nitric oxide

“…The NANC-induced relaxation of guinea-pig tracheal strips was abolished by tetrodotoxin, as previusly found by Ellis & Farmer (1989a). The effect of co-conotoxin GVIA on NANCinduced relaxations of guinea-pig tracheal smooth muscle was in accord with its effects on responses to cholinergic, noradrenergic and NANC nerve stimulation in a number of tissues (De Luca et al, 1990): responses to stimulation at 1 Hz were abolished and those to stimulation at 5 Hz were reduced.…”

Modulation of cholinergic neural bronchoconstriction by endogenous nitric oxide and vasoactive intestinal peptide in human airways in vitro.

“…a-Chymotrypsin, at a concentration shown to inhibit VIPinduced neural responses in guinea pig trachea (10) and abolish responses to exogenously applied VIP in human trachea ( 12,13 ), had no effect on cholinergic contractile responses to EFS. This suggests that endogenous VIP does not modulate cholinergic transmission in human trachea, exposing a marked difference from the guinea pig airways where both endogenous NO and VIP have been shown to inhibit cholinergic contractile responses ( 14).…”

“…This has been demonstrated by the partial inhibition of the i-NANC response by a-chymotrypsin, which abolishes responses to exogenously applied VIP (10), and by L-N0-monomethyl arginine (L-NMMA) and L-NG-nitroarginine methyl ester (L-NAME) (9), which are both potent and selective inhibitors of NO synthesis ( 11 ). In human trachea in vitro VIP is a potent smooth muscle relaxant (2) but no evidence has been found for endogenous VIP mediating the i-NANC response since concentrations of a-chymotrypsin that abolish the response to exogenously applied VIP have no effect on the i-NANC response ( 12,13).…”

l‐NG‐nitro arginine inhibits non‐adrenergic, non‐cholinergic relaxations of guinea‐pig isolated tracheal smooth muscle

“…In the guinea-pig, vasoactive intestinal peptide (VIP) and peptide histidine isoleucine (PHI) are strong candidates for at least part of this NANC relaxant response. Ellis & Farmer (1989b) have shown that a-chymotrypsin, in concentrations that selectively abolish responses to high concentrations of exogenous VIP and PHI, reduces inhibitory responses to NANC stimulation by about 35%. This raises the possibility that the remainder of the response is mediated by a nonpeptide substance.…”