Douglas S A, Beck G R, Elliott J D, Ohlstein E H
Department of Cardiovascular Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406-0939, USA.
J Cardiovasc Pharmacol. 1995;26 Suppl 3:S163-8.
The contractile responses to endothelin-1 (ET-1), endothelin-3 (ET-3), and sarafotoxin S6c (STXc) were best-fitted by a two-site model in the rabbit isolated saphenous vein. Agonists were equipotent at the high-affinity site (pD2s 12.0 +/- 0.2, 12.2 +/- 0.2, and 12.3 +/- 0.3, respectively), characteristic of an ETB receptor, whereas ET-3 and STXc were significantly more potent than ET-1 as vasoconstrictors at the low-affinity site (pD2s 10.2 +/- 0.3, 10.6 +/- 0.3, and 9.1 +/- 0.1, respectively), characteristic of an ETC-like receptor. The high affinity, ETB-mediated response was inhibited by SB 209670, Ro 47-0203, BQ-788, and Ro 46-2005 (Kbs of 0.15, 14, 110, and 280 nM against STXc, respectively) but was insensitive to PD 142893, RES-701 and BQ-123 (Kbs > or = 10 microM), consistent with this response being mediated by the ETB2-like receptor subtype. The low-affinity ETC-like-mediated component was inhibited by SB 209670, Ro 47-0203, BQ-788, Ro 46-2005, PD 142893, and RES-701 (Kbs 38 nM, 62 nM, 670 nM, 580 nM, 1.7 microM, and 2.0 microM, respectively), but was insensitive to BQ-123 (Kb > or = 10 microM). ET-3 produced endothelium-dependent vasorelaxation in the presence of active tone. Antagonist IC50s were approximated as being: SB 209670 3 nM; BQ-788 and RES 701,300 nM; Ro 46-2005 and PD 142893 3 microM; BQ-123 > or = 10 microM. These values were consistent with vasorelaxation being mediated by an ETB1-like receptor. Therefore, three pharmacologically distinct ET receptor subtypes have been identified in rabbit saphenous vein. Two contractile receptors, ETB2-like and ETC-like, are present on the vascular smooth-muscle receptor, whereas an ETB1-like receptor, which mediates the vasodilator actions of this peptide family, is present on the endothelium.
在兔离体隐静脉中，对内皮素-1（ET-1）、内皮素-3（ET-3）和铃蟾毒素S6c（STXc）的收缩反应最适合用双位点模型来拟合。激动剂在高亲和力位点的效价相同（pD2s分别为12.0±0.2、12.2±0.2和12.3±0.3），这是ETB受体的特征，而在低亲和力位点，ET-3和STXc作为血管收缩剂比ET-1显著更有效（pD2s分别为10.2±0.3、10.6±0.3和9.1±0.1），这是类ETC受体的特征。高亲和力的、由ETB介导的反应被SB 209670、Ro 47-0203、BQ-788和Ro 46-2005抑制（对STXc的Kbs分别为0.15、14、110和280 nM），但对PD 142893、RES-701和BQ-123不敏感（Kbs≥10 μM），这与该反应由ETB2样受体亚型介导一致。低亲和力的类ETC介导的成分被SB 20967所抑制0、Ro 47-0203、BQ-788、Ro 46-2005、PD 142893和RES-701（Kbs分别为38 nM、62 nM、670 nM、580 nM、1.7 μM和2.0 μM），但对BQ-123不敏感（Kb≥10 μM）。在有主动张力的情况下，ET-3产生内皮依赖性血管舒张。拮抗剂的IC50s约为：SB 209670 3 nM；BQ-788和RES 701为300 nM；Ro 46-2005和PD 142893为3 μM；BQ-123≥10 μM。这些值与血管舒张由ETB1样受体介导一致。因此，在兔隐静脉中已鉴定出三种药理学上不同的ET受体亚型。两种收缩性受体，即ETB2样和类ETC受体，存在于血管平滑肌上，而介导该肽家族血管舒张作用的ETB1样受体存在于内皮上。
