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Applied Study of VIP/PACAP Analogue in Asthma Therapy

VIP/PACAP类似物在哮喘治疗中的应用研究

基本信息

批准号：
13670833
负责人：
YOSHIHARA Shigemi
金额：
$ 0.9万
依托单位：
Dokkyo University School of Medicine
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2002
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13670833/
关键词：
Asthma Bronchodilator β2-adrenoceptor agonist Salbutamol PACAP 1-27 PACAP 1-27 analogue Airway smooth muscle Human bronchi β_2刺激薬

项目摘要

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.

本文比较了垂体腺苷酸环化酶激活肽（PACAP）1-27及其类似物[Arg_<152021>Leu_<17>]-PACAP-Gly-Lys-Arg-NH_2对离体人支气管的舒张作用。在卡巴胆碱浓度（0.1μM）预收缩的人支气管中，PACAP 1-27和沙丁胺醇累积给药引起浓度依赖性平滑肌松弛，具有相似的效力和最大松弛作用。PACAP 1-27类似物和原始PACAP 1-27的非累积给药引起浓度依赖性松弛，具有相似的最大松弛作用和效力。然而，PACAP 1-27类似物的作用的开始和抵消明显慢于原始PACAP 1 - 27（给药后5小时剩余的峰值舒张>90%对比<10%）。在人支气管中观察的3小时内，通过Captopril（10μM）和Phosphoramidon（1μM）抑制肽酶可显著增加PACAP 1 - 27的最大舒张作用和作用持续时间，但PACAP 1-27类似物则无此作用。结论：[Arg_<152021>Leu_<17>]-PACAP-Gly-Lys-Arg-NH_2对离体气道平滑肌有明显的浓度依赖性舒张作用。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更不易被肽酶切割。