Targeted disruption of the endothelin-B-receptor gene attenuates inflammatory nociception and cutaneous inflammation in mice

Endothelin-1 (ET-1) has been suggested to have a potential function as an i nflammatory mediator. The study reported here assessed the putative inflamm atory/nociceptive actions of the ET isopeptides using endothelin-B (ETB)-re ceptor knockout (KO) mice and ETA- (SB 234551) and ETB- (A192621) selective antagonists. Phenylbenzoquinone (PBQ)-induced algesia was evident in the w ild-type (WT) ETB (+/+) mice, attenuated by 80% in the heterozygous ETB (+/ -) mice, and absent in the ETB (-/-) homozygotes. This was reproduced pharm acologically in WT ETB (+/+) mice where the algesic effect of PBQ was inhib ited 74% by A192621, but unaffected by SE 234551 (both at 25 mg/kg p.o.). S imilar observations were made in a model of cutaneous inflammation: ETB (+/ +) mice had a marked inflammatory response to topical arachidonic acid, ETB (+/-) and ETB (-/-) mice had significantly reduced edema responses (37% an d 65% inhibition). Neutrophil infiltration was reduced in the ETB (+/-) and ETB (-/-) mice (51% and 65% reduction, respectively). Topical administrati on of A192621 (500 mug/ear) inhibited arachidonic acid-induced swelling (39 %) in WT ETB (+/+) mice. Collectively, these results support a role for the ETB-receptor in the mediation of inflammatory pain and cutaneous inflammat ory responses. As such, the development of ETB-receptor-selective antagonis ts may be of therapeutic utility in the treatment of inflammatory disorders .