Targeting endothelin ETA and ETB receptors inhibits antigen-induced neutrophil migration and mechanical hypernociception in mice.
Endothelin may contribute to the development of inflammatory events such as leukocyte recruitment and nociception. Herein, we investigated whether endothelin-mediated mechanical hypernociception (decreased nociceptive threshold, evaluated by electronic pressure-meter) and neutrophil migration (myeloperoxidase activity) are inter-dependent in antigen challenge-induced Th1-driven hind-paw inflammation. In antigen challenge-induced inflammation, endothelin (ET) ET(A) and ET(B) receptor antagonism inhibited both hypernociception and neutrophil migration. Interestingly, ET-1 peptide-induced hypernociception was not altered by inhibiting neutrophil migration or endothelin ET(B) receptor antagonism, but rather by endothelin ET(A) receptor antagonism. Furthermore, endothelin ET(A), but not ET(B), receptor antagonism inhibited antigen-induced PGE(2) production, whereas either selective or combined blockade of endothelin ET(A) and/or ET(B) receptors reduced hypernociception and neutrophil recruitment caused by antigen challenge. Concluding, this study advances knowledge into the role for endothelin in inflammatory mechanisms and further supports the potential of endothelin receptor antagonists in controlling inflammation.
Verri
Waldiceu A
WA
Department of Pharmacology, School of Medicine of Ribeirão Preto, University of São Paulo, Avenida Bandeirantes, 3900, 14049-900, Ribeirão Preto, São Paulo, Brazil. waldiceujr@yahoo.com.br
Cunha
Thiago M
TM
Magro
Danilo A
DA
Guerrero
Ana T G
AT
Vieira
Silvio M
SM
Carregaro
Vanessa
V
Souza
Guilherme R
GR
Henriques
Maria das Graças M O
Md
Ferreira
Sérgio H
SH
Cunha
Fernando Q
FQ
D000818:Animals; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D015232:Dinoprostone / Q000096:biosynthesis; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1 / Q000096:biosynthesis / Q000494:pharmacology; D006930:Hyperalgesia / Q000097:blood / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D007249:Inflammation / Q000097:blood / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009504:Neutrophils / Q000187:drug effects*; D010047:Ovalbumin / Q000276:immunology; D010147:Pain Measurement; D011312:Pressure; D012867:Skin / Q000187:drug effects / Q000276:immunology / Q000378:metabolism
D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1; D010047:Ovalbumin; D015232:Dinoprostone