title: Pharmacological effects and lung-binding characteristics of a novel VIP analogue, [R15, 20, 21, L17]-VIP-GRR (IK312532).
abstract: 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.
authors.affiliation: 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.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Ohmori
authors.forename: Shuji
authors.initials: S
authors.lastname: Maruyama
authors.forename: Ryohei
authors.initials: R
authors.lastname: Kimura
authors.forename: Satomi
authors.initials: S
authors.lastname: Onoue
authors.forename: Asami
authors.initials: A
authors.lastname: Matsumoto
authors.forename: Kosuke
authors.initials: K
authors.lastname: Endo
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Iwanaga
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Kashimoto
authors.forename: Shizuo
authors.initials: S
authors.lastname: Yamada
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D001980:Bronchi / Q000166:cytology / Q000187:drug effects; D006098:Granulocytes / Q000187:drug effects; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007700:Kinetics; D008168:Lung / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D009092:Mucous Membrane / Q000166:cytology / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D014132:Trachea / Q000187:drug effects; D014660:Vasoactive Intestinal Peptide / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*
chemical_list: D014660:Vasoactive Intestinal Peptide