Verri Waldiceu A, Cunha Thiago M, Magro Danilo A, Guerrero Ana T G, Vieira Silvio M, Carregaro Vanessa, Souza Guilherme R, Henriques Maria das Graças M O, Ferreira Sérgio H, Cunha Fernando Q
Department of Pharmacology, School of Medicine of Ribeirão Preto, University of São Paulo, Avenida Bandeirantes, 3900, 14049-900, Ribeirão Preto, São Paulo, Brazil.
Naunyn Schmiedebergs Arch Pharmacol. 2009 Mar;379(3):271-9. doi: 10.1007/s00210-008-0360-1. Epub 2008 Oct 15.
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.
内皮素可能参与诸如白细胞募集和痛觉感受等炎症事件的发生发展。在此，我们研究了在内抗原激发诱导的Th1驱动的后爪炎症中，内皮素介导的机械性痛觉过敏（通过电子压力计评估的痛觉阈值降低）和中性粒细胞迁移（髓过氧化物酶活性）是否相互依赖。在抗原激发诱导的炎症中，内皮素（ET）ET(A)和ET(B)受体拮抗剂抑制了痛觉过敏和中性粒细胞迁移。有趣的是，ET-1肽诱导的痛觉过敏不受抑制中性粒细胞迁移或内皮素ET(B)受体拮抗剂的影响，而是受内皮素ET(A)受体拮抗剂的影响。此外，内皮素ET(A)受体拮抗剂而非ET(B)受体拮抗剂抑制了抗原诱导的PGE(2)产生，而内皮素ET(A)和/或ET(B)受体的选择性或联合阻断减少了抗原激发引起的痛觉过敏和中性粒细胞募集。总之，本研究增进了对内皮素在炎症机制中作用的认识，并进一步支持了内皮素受体拮抗剂在控制炎症方面的潜力。
