Griswold D E, Douglas S A, Martin L D, Davis T G, Davis L, Ao Z, Luttmann M A, Pullen M, Nambi P, Hay D W, Ohlstein E H
Department of Pulmonary Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406-0939, USA.
J Cardiovasc Pharmacol. 2000 Nov;36(5 Suppl 1):S78-81. doi: 10.1097/00005344-200036051-00026.
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.
内皮素-1（ET-1）被认为具有作为炎症介质的潜在功能。本文报道的研究使用内皮素B（ET(B)）受体基因敲除（KO）小鼠以及ET(A) （SB 234551）和ET(B) （A192621）选择性拮抗剂，评估了ET异肽的假定炎症/伤害感受作用。苯醌（PBQ）诱导的痛觉过敏在野生型（WT）ET(B) （+/+）小鼠中明显，在杂合子ET(B) （+/-）小鼠中减弱了80%，而在ET(B) （-/-）纯合子小鼠中不存在。这在WT ET(B) （+/+）小鼠中通过药理学方法得以重现，其中PBQ的痛觉过敏效应被A192621抑制了74%，但不受SB 234551影响（两者均为口服25 mg/kg）。在皮肤炎症模型中也有类似观察结果：ET(B) （+/+）小鼠对局部花生四烯酸有明显的炎症反应，ET(B) （+/-）和ET(B) （-/-）小鼠的水肿反应显著降低（分别抑制37%和65%）。ET(B) （+/-）和ET(B) （-/-）小鼠的中性粒细胞浸润减少（分别减少51%和65%）。在WT ET(B) （+/+）小鼠中局部应用A192621（500 μg/耳）可抑制花生四烯酸诱导的肿胀（39%）。总体而言，这些结果支持ET(B)受体在介导炎症性疼痛和皮肤炎症反应中的作用。因此，ET(B)受体选择性拮抗剂的开发可能在炎症性疾病的治疗中具有治疗价值。
