title: Targeted disruption of the endothelin-B-receptor gene attenuates inflammatory nociception and cutaneous inflammation in mice.
abstract: 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 (ET(B))-receptor knockout (KO) mice and ET(A)- (SB 234551) and ET(B)- (A192621) selective antagonists. Phenylbenzoquinone (PBQ)-induced algesia was evident in the wild-type (WT) ET(B) (+/+) mice, attenuated by 80% in the heterozygous ET(B) (+/-) mice, and absent in the ET(B) (-/-) homozygotes. This was reproduced pharmacologically in WT ET(B) (+/+) 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: ET(B) (+/+) mice had a marked inflammatory response to topical arachidonic acid, ET(B) (+/-) and ET(B) (-/-) mice had significantly reduced edema responses (37% and 65% inhibition). Neutrophil infiltration was reduced in the ET(B) (+/-) and ET(B) (-/-) mice (51% and 65% reduction, respectively). Topical administration of A192621 (500 microg/ear) inhibited arachidonic acid-induced swelling (39%) in WT ET(B) (+/+) mice. Collectively, these results support a role for the ET(B)-receptor in the mediation of inflammatory pain and cutaneous inflammatory responses. As such, the development of ET(B)-receptor-selective antagonists may be of therapeutic utility in the treatment of inflammatory disorders.
authors.affiliation: Department of Pulmonary Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406-0939, USA.
authors.forename: D E
authors.initials: DE
authors.lastname: Griswold
authors.forename: S A
authors.initials: SA
authors.lastname: Douglas
authors.forename: L D
authors.initials: LD
authors.lastname: Martin
authors.forename: T G
authors.initials: TG
authors.lastname: Davis
authors.forename: L
authors.initials: L
authors.lastname: Davis
authors.forename: Z
authors.initials: Z
authors.lastname: Ao
authors.forename: M A
authors.initials: MA
authors.lastname: Luttmann
authors.forename: M
authors.initials: M
authors.lastname: Pullen
authors.forename: P
authors.initials: P
authors.lastname: Nambi
authors.forename: D W
authors.initials: DW
authors.lastname: Hay
authors.forename: E H
authors.initials: EH
authors.lastname: Ohlstein
mesh_terms: D000818:Animals; D016718:Arachidonic Acid / Q000494:pharmacology; D016227:Benzoquinones / Q000494:pharmacology; D003872:Dermatitis / Q000209:etiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D010146:Pain / Q000209:etiology*; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000235:genetics / Q000502:physiology*
chemical_list: D016227:Benzoquinones; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; D016718:Arachidonic Acid; C029322:phenylbenzoquinone