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.