Applied Study of VIP/PACAP Analogue in Asthma Therapy

我们比较了垂体腺苷酸环化酶激活肽（PACAP） 1-27与新开发的PACAP 1-27类似物[Arg_<152021>Leu_<17>]-PACAP-Gly-Lys-Arg-NH_2对体外人支气管的松弛作用。在经浓度（0.1μM）预先收缩的人支气管中，pacap1 -27和沙丁胺醇的累积给药可引起浓度依赖性的平滑肌松弛，其效果相似，且松弛效果最大。非累积性给药PACAP 1-27类似物和原PACAP 1-27引起浓度依赖性松弛，其最大松弛效果和效力也相似。然而，与原PACAP 1-27相比，PACAP 1-27类似物的作用起效和偏移明显慢于原PACAP 1-27（给药后5h的峰松弛率<10%）。卡托普利（10μM）和磷酰胺（1μM）对人支气管肽酶的抑制作用可显著增加PACAP 1-27的最大松弛效应和作用时间，但对PACAP 1-27类似物的作用时间无显著影响。我们得出结论，[Arg_<152021>Leu_<17>]-PACAP-Gly-Lys-Arg-NH_2在体外产生显著的、浓度依赖性的、持续的气道平滑肌松弛。持续的松弛作用至少部分是由于PACAP 1-27类似物比原始肽PACAP 1-27更不容易被肽酶切割。

We compared the relaxant effect of pituitary adenylate cyclase activating peptide (PACAP) 1-27 with that of a newly developed PACAP 1-27 analogue, [Arg_<152021>Leu_<17>]-PACAP-Gly-Lys-Arg-NH_2, in human bronchi in vitro. In human bronchi precontracted by carbachol concentration (0.1μM), cumulative administration of PACAP 1-27 and salbutamoi caused concentration-dependent smooth muscle relaxation with similar potencies and maximum relaxant effects. Non-cumulative administration of the PACAP 1-27 analogue and the original PACAP 1-27 caused concentration-dependent relaxation with a similar maximum relaxant effect and potency as well. However, the onset and offset of action was markedly slower for the PACAP 1-27 analogue than for the original PACAP 1-27 (>90% versus <10% of peak relaxation remaining 5h after administration). Peptidase inhibition by captopril (10μM) and phosphoramidon (1μM) significantly increased the maximum relaxant effect and duration of action of PACAP 1-27 but not of the PACAP 1-27 analogue, during the 3h of observation in the human bronchi. We conclude that [Arg_<152021>Leu_<17>]-PACAP-Gly-Lys-Arg-NH_2 produce significant, concentration-dependent and sustained airway smooth muscle relaxation in vitro. The sustained relaxant effect is due, at least in part, to the PACAP 1-27 analogue being less susceptible to cleavage by peptidases than the original peptide PACAP 1-27.