Endothelin-1 (ET-1) has been suggested to have a potential function as an inflammatory mediator. The study reported here assessed the putative inflammatory/nociceptive actions of the ET isopeptides using endothelin-B (ETB)-receptor knockout (KO) mice and ETA- (SB 234551) and ETB- (A192621) selective antagonists. Phenylbenzoquinone (PBQ)-induced algesia was evident in the wild-type (WT) ETB (+/+) mice, attenuated by 80% in the heterozygous ETB (+/−) mice, and absent in the ETB (−/−) homozygotes. This was reproduced pharmacologically in WT ETB (+/+) mice where the algesic effect of PBQ was inhibited 74% by A192621, but unaffected by SB 234551 (both at 25 mg/kg p.o.). Similar 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% and 65% inhibition). Neutrophil infiltration was reduced in the ETB (+/−) and ETB (−/−) mice (51% and 65% reduction, respectively). Topical administration of A192621 (500 μg/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 inflammatory responses. As such, the development of ETB-receptor-selective antagonists may be of therapeutic utility in the treatment of inflammatory disorders.
Departments of *Pulmonary Pharmacology, †Cardiovascular Pharmacology, ‡Immunology, §Laboratory Animal Science, and ¶Renal Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania, U.S.A.
Address correspondence and reprint requests to Douglas W.P. Hay, Director Group, Department of Pulmonary Biology, SmithKline Beecham Pharmaceuticals, 709 Swedeland Road, King of Prussia, PA 19406-0939, U.S.A.
© 2000 Lippincott Williams & Wilkins, Inc.