title: The non-peptide kinin receptor antagonists FR 173657 and SSR 240612: preclinical evidence for the treatment of skin inflammation.
abstract: 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.
authors.affiliation: Department of Pharmacology, Universidade Federal do Paraná, Curitiba, PR, Brazil.
authors.forename: Evelise Fernandes
authors.initials: EF
authors.lastname: Pietrovski
authors.forename: Michel Fleith
authors.initials: MF
authors.lastname: Otuki
authors.forename: Domenico
authors.initials: D
authors.lastname: Regoli
authors.forename: Michael
authors.initials: M
authors.lastname: Bader
authors.forename: João Bosco
authors.initials: JB
authors.lastname: Pesquero
authors.forename: Daniela Almeida
authors.initials: DA
authors.lastname: Cabrini
authors.forename: Aleksander Roberto
authors.initials: AR
authors.lastname: Zampronio
mesh_terms: D000818:Animals; D065169:Bradykinin B1 Receptor Antagonists; D065094:Bradykinin B2 Receptor Antagonists; D002211:Capsaicin / Q000008:administration & dosage; D003872:Dermatitis / Q000188:drug therapy*; D004149:Dioxoles / Q000008:administration & dosage / Q000627:therapeutic use*; D005260:Female; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011804:Quinolines / Q000008:administration & dosage / Q000627:therapeutic use*; D043783:Receptor, Bradykinin B1 / Q000235:genetics / Q000378:metabolism; D043782:Receptor, Bradykinin B2 / Q000235:genetics / Q000378:metabolism; D013449:Sulfonamides / Q000008:administration & dosage / Q000627:therapeutic use*
chemical_list: C487113:2-((3-(1,3-benzodioxol-5-yl)-3-(((6-methoxy-2-naphthyl)sulfonyl)amino)propanoyl)amino)-3-(4-((2,6-dimethylpiperidinyl)methyl)phenyl)-N-isopropyl-N-methylpropanamide; D065169:Bradykinin B1 Receptor Antagonists; D065094:Bradykinin B2 Receptor Antagonists; D004149:Dioxoles; C105311:FR 173657; D011804:Quinolines; D043783:Receptor, Bradykinin B1; D043782:Receptor, Bradykinin B2; D013449:Sulfonamides; D002211:Capsaicin