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Duration of relaxant action of an analogue of pituitary adenylate cyclase activating peptide (PACAP)-27, [Arg‘5~2°~2‘, Leull]-PACAP-27-NH2, was compared with that of PACAP-27 in the smooth muscle isolated from guinea-pig trachea. The relaxant action was examined on the prolonged contracted state of the smooth muscle, which had been stimulated with carbachol (CCh; 0.1 /1M). Addition of the analogue caused concentration-dependent relaxation; both the onset and offset of which were much slower than those with PACAP-27, vasoactive intestinal polypeptide (VIP), and peptide histidine isoleucine (PHI). More than 90% of the maximum relaxation was maintained for 6h after addition of the analogue, whereas the relaxation induced by PACAP-27, VIP, and PHI reached a maximum by 20 min after the addition and was followed by gradual contraction. Influence of peptidases involved in the smooth muscle preparation on the peptides was examined using 10 ;,¢M captopril and 1/1M phosphoramidon as peptidase inhibitors. Although the efficacy and duration of the relaxant action with PACAP-27 were significantly potentiated in the presence of peptidase inhibitors, those with the analogue were only slightly affected. A conclusion is drawn that the analogue has sustained relaxant action on CCh-induced contraction of the tracheal smooth muscle, and that this sustained action is, at least in part, due to much lower susceptibility of the analogue to degradation by peptidases, implying an advantage of the analogue in clinical application. Two endogenous derivatives of pituitary adenylate cyclase activating peptide (PACAP) have been identified, PACAP-27 and PACAP-38 (13, 14). PACAPs has been shown to exist in airways in various species including humans (5, 12). Recent studies in rodents showed that these peptides produce tracheal smooth muscle relaxation in vitro (8) and bronchodilation in vivo (ll), and this relaxation might be mediated by cyclic AMP (1). PACAP-27 produces weaker cardiovascular effects, when compared with that of PACAP-38 and “Correspondence to: S. Yoshihara at the above address. Tel: (81) 282-87-2155; Fax: (81) 282-86-7521 vasoactive intestinal polypeptide (VIP) in rats and dogs ('7, 15), and of salbutamol in guinea pigs in vivo (11). Previously, we have synthesized several PACAP and VIP analogues, including [Arg‘5~2°~2‘, Leun]-PACAP-27-NH2 (Fig. 1), [Argl5’2°*2‘, Leu”]PACAP-27-Gly-Lys-Arg-NH2, [Arg'5'2°-2‘, Leu'7] VIP and [Arg‘5=2°’2', Leun] VIP-Gly-Lys-Arg-NH2. Among these analogues, both [Arg'5*2°’2‘, Leu”]PACAP-27-Gly-Lys-Arg-NH2 and [Arg‘5*2°~2‘, Leu”]-PACAP-27-NH2 showed significantly sustained relaxant action on the guinea-pig smooth muscle relaxation in vitro (9). Subsequently, we reported that [Arg‘5=2°'2', Leu”]-PACAP-27-GlyLys-Arg-NH2 produced significant concentration-

SUSTAINED RELAXANT ACTION OF [Arg15,20,21, Leu17]-PACAP-27—NH2 ON CARBACHOL-INDUCED CONTRACTION OF GUINEA-PIG TRACHEAL SMOOTH MUSCLE IN VITRO