Leite-Moreira Adelino F, Brás-Silva Carmen, Pedrosa Carla
Serviço de Fisiologia, Faculdade de Medicina, Universidade do Porto, Porto.
Rev Port Cardiol. 2002 Sep;21(9):1009-16.
Endothelin-1 (ET-1) is an endogenous peptide whose effects are mediated by two distinct types of receptors, ETA and ETB. Whereas the ETA receptors promote vasoconstriction and mitogenesis and increase inotropism, ETB receptors have vasodilatory and anti-mitogenic properties mediated by nitric oxide release. In this study we investigated the myocardial effects of selective ETB receptor stimulation.
The study was performed on right papillary muscles (n = 30) from New Zealand white rabbits (Krebs-Ringer; 1.8 mM CaCl2; 35 degrees C). The effects of selective ETB receptor activation by Sarafotoxin S6c (0.2 microM; n = 6) and of non-selective ETA and ETB receptor activation by ET-1 (1 nM; n = 9) were studied. The effects of ET-1 were also evaluated in the presence of a selective ETA receptor antagonist, BQ-123 (0.1 microM; n = 9) and of a selective ETB receptor antagonist BQ-788 (0.1 microM; n = 6). Only significant results (mean +/- SE; p < 0.05) are given, expressed as % baseline.
Sarafotoxin S6c reduced active tension (AT) by 8.1 +/- 5.5% and peak rate of tension development (dT/dtmax) by 8.6 +/- 5.6%. Alone, ET-1 increased AT by 64.2 +/- 18.2% and dT/dtmax by 58.6 +/- 20.2%. These effects of ET-1 were exacerbated in the presence of BQ-788 (AT increased by 82.6 +/- 17.5% and dT/dtmax by 121.3 +/- 26.6%) and inverted in the presence of BQ-123 (AT decreased by 12.8 +/- 2.7% and dT/dtmax by 16.1 +/- 3.0%).
This study demonstrates, for the first time, that selective stimulation of ETB receptors has a negative inotropic effect. Detailed characterization of the effects of stimulation of each type of ET-1 receptor is of particular relevance as selective and non-selective inhibitors of these receptors are currently being tested for treatment of heart failure.
内皮素 -1（ET-1）是一种内源性肽，其作用由两种不同类型的受体介导，即ETA和ETB。ETA受体促进血管收缩、有丝分裂并增强心肌收缩力，而ETB受体具有通过释放一氧化氮介导的血管舒张和抗有丝分裂特性。在本研究中，我们研究了选择性刺激ETB受体对心肌的影响。
本研究在新西兰白兔的右乳头肌（n = 30）上进行（Krebs-Ringer液；1.8 mM氯化钙；35℃）。研究了Sarafotoxin S6c（0.2 microM；n = 6）选择性激活ETB受体以及ET-1（1 nM；n = 9）非选择性激活ETA和ETB受体的作用。还评估了在选择性ETA受体拮抗剂BQ-123（0.1 microM；n = 9）和选择性ETB受体拮抗剂BQ-788（0.1 microM；n = 6）存在的情况下ET-1的作用。仅给出显著结果（平均值±标准误；p < 0.05），以相对于基线的百分比表示。
Sarafotoxin S6c使主动张力（AT）降低8.1±5.5%，张力发展的峰值速率（dT/dtmax）降低8.6±5.6%。单独使用时，ET-1使AT增加64.2±18.2%，dT/dtmax增加58.6±20.2%。在BQ-788存在的情况下，ET-1的这些作用加剧（AT增加82.6±17.5%，dT/dtmax增加121.3±26.6%），而在BQ-123存在的情况下则相反（AT降低12.8±2.7%，dT/dtmax降低16.1±3.0%）。
本研究首次证明，选择性刺激ETB受体具有负性肌力作用。鉴于目前正在测试这些受体的选择性和非选择性抑制剂用于治疗心力衰竭，详细表征每种类型的ET-1受体刺激的作用具有特别重要的意义。
