The non-peptide kinin receptor antagonists FR 173657 and SSR 240612: Preclinical evidence for the treatment of skin inflammation

Peptide and non-peptide kinin receptor antagonists were evaluated in cutaneous inflammation models in mice. Topical and i.p. application of kinin B₁ and B₂ receptor antagonists caused a significant inhibition of the capsaicin-induced cutaneous neurogenic inflammatory response. The calculated mean ID₅₀ for Hoe140 and SSR240612 were 23.83 (9.14-62.14) nmol/kg and 0.23 (0.15-0.36) mg/ear, respectively. The I_max observed for Hoe140, SSR240612, R-715, FR173657, and FR plus SSR were 61 ± 5%, 56 ± 3%, 65 ± 10%, 48 ± 8%, and 52 ± 4%, respectively. Supporting these results, double B₁ and B₂ kinin receptors knockout mice showed a significant inhibition of capsaicin-induced ear oedema (42 ± 7%). However, mice with a single deletion of either B₁ or B₂ receptors exhibited no change in their capsaicin responses. In contrast, all of the examined kinin receptor antagonists were unable to inhibit the oedema induced by TPA and the results from knockout mice confirmed the lack of kinin receptor signaling in this model. These findings show that kinin receptors are present in the skin and that both kinin receptors seem to be important in the neurogenic inflammatory response. Moreover, non-peptide antagonists were very effective in reducing skin inflammation when topically applied, thereby suggesting that they could be useful tools in the treatment of some skin inflammatory diseases.