Pietrovski Evelise Fernandes, Otuki Michel Fleith, Regoli Domenico, Bader Michael, Pesquero João Bosco, Cabrini Daniela Almeida, Zampronio Aleksander Roberto
Department of Pharmacology, Universidade Federal do Paraná, Curitiba, PR, Brazil.
Regul Pept. 2009 Jan 8;152(1-3):67-72. doi: 10.1016/j.regpep.2008.10.005. Epub 2008 Nov 1.
Peptide and non-peptide kinin receptor antagonists were evaluated in cutaneous inflammation models in mice. Topical and i.p. application of kinin B(1) and B(2) receptor antagonists caused a significant inhibition of the capsaicin-induced cutaneous neurogenic inflammatory response. The calculated mean ID(50) 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 B(1) and B(2) kinin receptors knockout mice showed a significant inhibition of capsaicin-induced ear oedema (42+/-7%). However, mice with a single deletion of either B(1) or B(2) 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.
在小鼠皮肤炎症模型中对肽类和非肽类激肽受体拮抗剂进行了评估。局部和腹腔注射激肽B(1)和B(2)受体拮抗剂可显著抑制辣椒素诱导的皮肤神经源性炎症反应。计算得出的Hoe140和SSR240612的平均半数抑制剂量(ID50)分别为23.83(9.14 - 62.14)nmol/kg和0.23(0.15 - 0.36)mg/耳。观察到的Hoe140、SSR240612、R - 715、FR173657和FR加SSR的最大抑制率(I(max))分别为61±5%、56±3%、65±10%、48±8%和52±4%。支持这些结果的是，双B(1)和B(2)激肽受体敲除小鼠对辣椒素诱导的耳部水肿有显著抑制作用(42±7%)。然而，单缺失B(1)或B(2)受体的小鼠对辣椒素的反应没有变化。相反，所有检测的激肽受体拮抗剂均无法抑制佛波酯(TPA)诱导的水肿，敲除小鼠的结果证实了该模型中缺乏激肽受体信号传导。这些发现表明皮肤中存在激肽受体，并且两种激肽受体似乎在神经源性炎症反应中都很重要。此外，非肽类拮抗剂局部应用时在减轻皮肤炎症方面非常有效，因此表明它们可能是治疗某些皮肤炎症性疾病的有用工具。
