Endothelins and endothelin receptor antagonists -: Therapeutic considerations for a novel class of cardiovascular drugs
Endothelins and endothelin receptor antagonists -: Therapeutic considerations for a novel class of cardiovascular drugs
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DOI：
10.1161/01.cir.102.19.2434
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发表时间：
2000-11-07
期刊：
影响因子：
37.8
通讯作者：
Barton, M
中科院分区：
文献类型：
--
作者：
Lüscher, TF;Barton, M
由21个氨基酸组成的内皮素-1（ET-1）是内皮素肽家族的主要亚型，该家族包括ET-2、ET-3和ET-4。它发挥各种生物学作用，包括血管收缩和刺激心血管系统内外组织中的细胞增殖。ET-1由内皮素转化酶（ECE）、糜酶和非ECE金属蛋白酶合成;在血管和非血管细胞中以自分泌方式调节。ET-1通过激活G（i）-蛋白偶联受体发挥作用。ETA受体介导血管收缩和细胞增殖，而ETB受体对于ET-1的清除、内皮细胞存活、一氧化氮和前列环素的释放以及ECE-1的抑制是重要的。ET在高血压、动脉粥样硬化、再狭窄、心力衰竭、特发性心肌病和肾衰竭中被激活。组织浓度更可靠地反映了ET系统的激活，因为血管ET-1水平的增加发生在血浆中没有变化的情况下。利用ET系统的分子和药理学抑制的实验研究和第一个临床试验已经证明ET-1参与正常的心血管稳态。因此，ET-1主要通过压力非依赖性机制在动脉和肺动脉高压、肾小球硬化、动脉粥样硬化和心力衰竭中观察到的功能和结构变化中起主要作用。ET拮抗剂是治疗心血管疾病的新药物。
The 21-amino acid peptide endothelin-1 (ET-1) is the predominant isoform of the endothelin peptide family, which includes ET-2, ET-3, and ET-4. It exerts various biological effects, including vasoconstriction and the stimulation of cell proliferation in tissues both within and outside of the cardiovascular system. ET-1 is synthesized by endothelin-converting enzymes (ECE), chymases, and non-ECE metalloproteases; it is regulated in an autocrine fashion in vascular and nonvascular cells. ET-1 acts through the activation of G(i)-protein-coupled receptors. ETA receptors mediate vasoconstriction and cell proliferation, whereas ETB receptors are important for the clearance of ET-1, endothelial cell survival, the release of nitric oxide and prostacyclin, and the inhibition of ECE-1.ET is activated in hypertension, atherosclerosis, restenosis, heart failure, idiopathic cardiomyopathy, and renal failure. Tissue concentrations more reliably reflect the activation of the ET system because increased vascular ET-1 levels occur in the absence of changes in plasma. Experimental studies using molecular and pharmacological inhibition of the ET system and the first clinical trials have demonstrated that ET-1 takes part in normal cardiovascular homeostasis. Thus, ET-1 plays a major role in the functional and structural changes observed in arterial and pulmonary hypertension, glomerulosclerosis, atherosclerosis, and heart failure, mainly through pressure-independent mechanisms. ET antagonists are promising new agents in the treatment of cardiovascular diseases.