Pharmacological characterization of the vascular permeability enhancing effects of kinins in the rabbit skin.

Abstract

We have studied the increase of vascular permeability produced by kinins in rabbit dermis using the measurement of the exudation of a protein-bound dye (Evans blue) following the local injections of peptides.Representatives of four peptide groups having kinin-like pharmacological properties have been tested in this system at doses ranging from 10−12 to 10−9 mol: they are bradykinin (BK), substance P, bombesin, and the C-terminal octapeptide of cholecystokinin. Only BK has appreciable effects at the utilised doses.In order to identify the type of receptor mediating the effect of kinins in this system, the following order of potency of agonist analogues has been measured: [Tyr(Me)8]-BK > kallidin (KD) > BK > des-Arg9-BK. Moreover the B1 receptor antagonist, des-Arg10-[Leu9]-KD, was found to be inactive as inhibitor of the increase of permeability produced by BK. These facts suggest that bradykinin may activate B2 receptors in this system.In order to assess the participation of other endogenous mediators to the effect of BK on vascular permeability, mixed solutions of BK and indomethacin or BK and mepyramine were injected in the rabbit dermis. Indomethacin (0,1 – 1 μg) did not modify the responses to BK while mepyramine (10 μg) significantly reduced the effects of the lowest doses of BK. This finding was taken as an indication of the possible participation of tissue histamine to the increased vascular permeability evoked by BK. It is concluded that the blueing assay of the rabbit dermis is a distinctive system (a) which is specific for BK-related kinins, (b) in which the effects of BK may be mediated by B2 receptors, and (c) in which the action of BK may be partially mediated by histamine but is probably not mediated by arachidonic acid metabolites.