[LEU(8)]DES-ARG(9)-BRADYKININ INHIBITS THE ANGIOGENIC EFFECT OF BRADYKININ AND INTERLEUKIN-1 IN RATS

Subcutaneous implantation of sterile polyether sponges in rats elicited a reproducible neovascular response over 14 days, as determined by measurements of relative sponge blood flow by a Xe-133 clearance technique. The angiogenic response was verified by quantitation of haemoglobin contents and histological evaluation of vascularized sponges. Daily administration of 1 nmol of bradykinin (BK) into the implants significantly enhanced the basal sponge-induced neovascularization, leading to higher Xe-133 clearance values, increased haemoglobin contents, cellularity and vascularity. When given alone, lower doses of BK (10 pmol) or recombinant human interleukin-1 alpha (IL-1alpha 0.3 pmol) produced no apparent effects on the basal sponge-induced angiogenesis. However, co-administration of these two peptides produced an angiogenic response similar to that elicited by 1 nmol of BK. The BK/IL-1alpha-induced neovascularization was abolished by the bradykinin B1 receptor antagonist, [Leu8]des-Arg9-BK (1 nmol day-1), but not by the B2 receptor antagonist Ac-D-Arg-[Hyp3,D-Phe7,Leu8]-BK (1 nmol day-1). Thus, if such interaction between BK and IL-1alpha contributes to the excessive neovascularization in chronic inflammatory diseases, the blockade of B1 receptors may provide an effective treatment.