The endothelins comprise three structurally similar 21-amino acid peptides. Endothelin-1 and -2 activate two G-protein coupled receptors, ETA and ETB, with equal affinity, whereas endothelin-3 has a lower affinity for the ETA subtype. Genes encoding the peptides are present only among vertebrates. The ligand-receptor signaling pathway is a vertebrate innovation and may reflect the evolution of endothelin-1 as the most potent vasoconstrictor in the human cardiovascular system with remarkably long lasting action. Highly selective peptide ETA and ETB antagonists and ETB agonists together with radiolabeled analogs have accurately delineated endothelin pharmacology in humans and animal models, although surprisingly no ETA agonist has been discovered. ET antagonists (bosentan, ambrisentan) have revolutionized the treatment of pulmonary arterial hypertension, with the next generation of antagonists exhibiting improved efficacy (macitentan). Clinical trials continue to explore new applications, particularly in renal failure and for reducing proteinuria in diabetic nephropathy. Translational studies suggest a potential benefit of ETB agonists in chemotherapy and neuroprotection. However, demonstrating clinical efficacy of combined inhibitors of the endothelin converting enzyme and neutral endopeptidase has proved elusive. Over 28 genetic modifications have been made to the ET system in mice through global or cell-specific knockouts, knock ins, or alterations in gene expression of endothelin ligands or their target receptors. These studies have identified key roles for the endothelin isoforms and new therapeutic targets in development, fluid-electrolyte homeostasis, and cardiovascular and neuronal function. For the future, novel pharmacological strategies are emerging via small molecule epigenetic modulators, biologicals such as ETB monoclonal antibodies and the potential of signaling pathway biased agonists and antagonists.

中文翻译：

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 内皮素。


内皮素包含三种结构相似的 21 个氨基酸肽。内皮素1和-2以相同的亲和力激活两种G蛋白偶联受体ETA和ETB，而内皮素3对ETA亚型的亲和力较低。编码这些肽的基因仅存在于脊椎动物中。配体-受体信号通路是脊椎动物的一项创新，可能反映了内皮素-1作为人类心血管系统中最有效的血管收缩剂的进化，具有非常持久的作用。高选择性肽 ETA 和 ETB 拮抗剂以及 ETB 激动剂与放射性标记类似物一起准确描述了人类和动物模型中的内皮素药理学，尽管令人惊讶的是尚未发现 ETA 激动剂。 ET 拮抗剂（波生坦、安布里生坦）彻底改变了肺动脉高压的治疗，下一代拮抗剂（马西腾坦）的疗效得到了改善。临床试验继续探索新的应用，特别是在肾衰竭和减少糖尿病肾病蛋白尿方面。转化研究表明 ETB 激动剂在化疗和神经保护方面具有潜在益处。然而，证明内皮素转化酶和中性内肽酶联合抑制剂的临床疗效已被证明是难以捉摸的。通过整体或细胞特异性敲除、敲入或内皮素配体或其靶受体基因表达的改变，对小鼠的 ET 系统进行了超过 28 项遗传修饰。这些研究确定了内皮素亚型的关键作用以及在发育、液体电解质稳态以及心血管和神经元功能中的新治疗靶点。 未来，通过小分子表观遗传调节剂、ETB 单克隆抗体等生物制剂以及信号通路偏向激动剂和拮抗剂的潜力，新的药理学策略正在出现。