Targeting endothelin ETA and ETB receptors inhibits antigen-induced neutrophil migration and mechanical hypernociception in mice
The role of endothelin B (ET(B)) receptors in inflammation and nociception was examined using ET(B) receptor knockout mice. Genotyping studies were used with tissues from ET(B)((+/+)), ET(B)((+/-)), and ET(B)((-/-)) mice to confirm the loss of ET(B) receptors. Algesia induced by phenylbenzoquinone was evident in the (+/+) mice, reduced by approximately 80% in the (+/-) mice, and absent in the (-/-) mice. Phenylbenzoquinone-induced algesia in (+/+) mice was inhibited 74% by the ET(B) receptor-selective antagonist A192621 (25 mg/kg p.o.), but unaffected by the ET(A) receptor-selective antagonist SB 234551 (25 mg/kg p.o.). Noninflammatory pain, induced by hotplate, was equivalent between (+/+) and (-/-) mice. The cutaneous inflammatory response to topical arachidonic acid (AA) also was evaluated. Whereas (+/+) mice had a marked inflammatory response to AA, the (+/-), and (-/-) mice had significantly reduced fluid phase responses (37 and 65% inhibition, respectively). Neutrophil infiltration also was reduced in the (+/-) and (-/-) mice (51 and 65% reduction, respectively). Topical administration of A192621 (500 microg/ear) in (+/+) mice inhibited AA-induced swelling (39%), whereas SB 234551 (500 microg/ear) was without effect. Collectively, these results implicate the ET(B) receptor in mediation of inflammatory pain and cutaneous inflammatory responses in mice.