Ohmori Yuki, Maruyama Shuji, Kimura Ryohei, Onoue Satomi, Matsumoto Asami, Endo Kosuke, Iwanaga Toshihiko, Kashimoto Kazuhisa, Yamada Shizuo
Department of Biopharmaceutical Sciences and COE Program in the 21st Century, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Shizuoka 422-8526, Japan.
Regul Pept. 2004 Dec 15;123(1-3):201-7. doi: 10.1016/j.regpep.2004.04.029.
A novel VIP derivative, [R15, 20, 21, L17]-VIP-GRR (IK312532), relaxed potently the carbachol-induced contraction of guinea-pig isolated trachea with longer duration than that induced by VIP. IK312532 competed with [125I]VIP for the binding sites in the rat lung in a concentration-dependent manner. There was considerable decrease in specific [125I]VIP binding in each lobe of right and left lung 0.5 h after the intratracheal administration of IK312532 (50 microg/rat) as dry powder inhaler (DPI). Rosenthal analysis revealed that the administration of IK312532 (50 and 100 microg/rat)-DPI brought about a significant decrease of maximal number of binding sites (Bmax) for specific [125I]VIP binding in anterior and posterior lobes of rat right lung, suggesting a significant occupancy of lung VIP receptors. This effect by IK312532 in the posterior lobe of the right lung was dose-dependent and lasted until at least 2 h after the intratracheal administration. Furthermore, the antigen-evoked infiltration of granulocytes in the rat bronchiolar mucosa was markedly suppressed by the intratracheal administration of IK312532 (50 microg/rat)-DPI. In conclusion, the present study has shown that IK312532 exhibits long-lasting relaxation of tracheal smooth muscles and that the intratracheal administration of this peptide exerts a significant occupancy of lung VIP receptors as well as a suppression of the antigen-evoked infiltration of granulocytes in the bronchiolar mucosa. Thus, the formulation of IK312532 as DPI may be a pharmacologically useful drug delivery system for the therapy of pulmonary diseases such as asthma.
一种新型血管活性肠肽（VIP）衍生物，[R15, 20, 21, L17]-VIP-GRR（IK312532），能有效松弛豚鼠离体气管由卡巴胆碱诱导的收缩，且作用持续时间比VIP诱导的更长。IK312532在大鼠肺中与[125I]VIP竞争结合位点，呈浓度依赖性。以干粉吸入器（DPI）形式气管内给予IK312532（50微克/只大鼠）后0.5小时，左右肺各叶中特异性[125I]VIP结合显著减少。罗森塔尔分析显示，给予IK312532（50和100微克/只大鼠）-DPI后，大鼠右肺前后叶中特异性[125I]VIP结合的最大结合位点数（Bmax）显著降低，表明肺VIP受体被大量占据。IK312532对右肺后叶的这种作用呈剂量依赖性，且在气管内给药后至少持续2小时。此外，气管内给予IK312532（50微克/只大鼠）-DPI可显著抑制大鼠细支气管黏膜中抗原诱发的粒细胞浸润。总之，本研究表明IK312532对气管平滑肌有持久的松弛作用，且气管内给予该肽可显著占据肺VIP受体，并抑制细支气管黏膜中抗原诱发的粒细胞浸润。因此，将IK312532制成DPI剂型可能是治疗哮喘等肺部疾病的一种药理学上有用的药物递送系统。
