Beck G R, Douglas S A, 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:S385-8.
This study examined the effect of peptide and nonpeptide endothelin (ET) receptor antagonists on the contractile actions of ET-1 and sarafotoxin S6c (STXc) in the rabbit isolated pulmonary artery (RbPA). The peptide antagonists BQ-123, BQ-788, and RES-701 (10 microM) did not inhibit ET-1-induced RbPA contractions. The nonpeptide antagonists PD 156123, Ro 47-0203, and SB 217242 (10 microM) also had no effect on ET-1--induced contractions. In contrast, the nonpeptide antagonists SB 209670 and L-749,239 (10 microM) both caused a shift to the right of the ET-1 concentration-response curve (Kbs of 231 nM and 1.42 microM, respectively) and a two- to three-fold increase in nH (Hill slope), without altering the Rmax (maximal agonist-induced contraction). Contractile responses to STXc were unaffected by BQ-123, RES-701, and PD 156123 (10 microM). SB 209670, SB 217242, L-749,239, Ro 47-0203, and BQ-788 (10 microM) caused a shift to the right of the STXc response curve (Kbs of 16, 353, 202, 1,303 and 1,499 nM, respectively) and an increase in nH and Rmax. SB 209670 and L-749,239 were both approximately 10-fold more potent in antagonizing STXc than ET-1. Assuming, at best, Kbs of 10 microM for SB 217242, Ro 47-0203, and BQ-788 against ET-1, these antagonists were also at least 10-fold more potent in blocking STXc. The effects of various incubation and washout times on the antagonistic properties of SB 209670 (1 microM) against STXc were studied. Washing the antagonist from the tissue bath caused a 100-fold decrease in affinity (Kbs of 23-2,373 nM at 0 and 30 min, respectively) and a return to near control levels of nH (within 30 min). In contrast, the augmented Rmax response did not return to control levels until 6 hr later. As the incubation time was increased, the augmented Rmax was sustained (6 h), but affinity decreased (Kbs of 21 and 793 nM after 5 min and 6 h of incubation), and nH returned to near control values. In conclusion, agonist-dependent inhibition by ETB receptor antagonists is observed in the RbPA. Heterogenous populations of ET receptors, differential binding domains, and/or functionally uncoupled receptors may account for this phenomenon.
本研究检测了肽类和非肽类内皮素（ET）受体拮抗剂对兔离体肺动脉（RbPA）中ET-1和铃蟾毒素S6c（STXc）收缩作用的影响。肽类拮抗剂BQ-123、BQ-788和RES-701（10微摩尔）不抑制ET-1诱导的RbPA收缩。非肽类拮抗剂PD 156123、Ro 47-0203和SB 217242（10微摩尔）对ET-1诱导的收缩也无作用。相反，非肽类拮抗剂SB 209670和L-749,239（10微摩尔）均使ET-1浓度-反应曲线右移（Kb分别为231纳摩尔和1.42微摩尔），且希尔斜率（nH）增加2至3倍，而不改变最大反应（最大激动剂诱导的收缩）。对STXc的收缩反应不受BQ-123、RES-701和PD 156123（10微摩尔）影响。SB 209670、SB 217242、L-749,239、Ro 47-0203和BQ-788（10微摩尔）使STXc反应曲线右移（Kb分别为16、353、202、1303和1499纳摩尔），并使nH和最大反应增加。SB 209670和L-749,239拮抗STXc的效力比拮抗ET-1的效力约高10倍。假设SB 217242、Ro 47-0203和BQ-788对ET-1的Kb至多为10微摩尔，这些拮抗剂阻断STXc的效力也至少高10倍。研究了不同孵育和洗脱时间对SB 209670（1微摩尔）拮抗STXc特性的影响。从组织浴中洗去拮抗剂导致亲和力下降100倍（0分钟和30分钟时的Kb分别为23至2373纳摩尔），nH在30分钟内恢复至接近对照水平。相反，增强的最大反应直到6小时后才恢复至对照水平。随着孵育时间增加，增强的最大反应持续存在（6小时），但亲和力下降（孵育5分钟和6小时后的Kb分别为21和793纳摩尔），nH恢复至接近对照值。总之，在RbPA中观察到ETB受体拮抗剂的激动剂依赖性抑制作用。ET受体的异质性群体、不同的结合域和/或功能解偶联的受体可能是这一现象的原因。
