[Ala1,3,11,15]-Endothelin is a modified linear analogue of endothelin-1, characterized by the substitution of alanine for the native amino acids at positions 1, 3, 11, and 15 of the original sequence[1-2]. [Ala1,3,11,15]-Endothelin acts as a selective endothelin B (ETB) receptor agonist with an IC₅₀ ranging from 0.33nM to 0.61nM and is commonly used in studies related to vasoconstriction and receptor function[3-4].
In vitro, when Chinese hamster ovary (CHO) cells stably expressing human ETB receptors were treated with 100nM [Ala1,3,11,15]-Endothelin for 20 minutes, [Ala1,3,11,15]-Endothelin significantly stimulated cytosolic phospholipase A₂ activity and promoted prostaglandin E₂ secretion[5]. In wounded human umbilical vein endothelial cell (HUVEC) monolayers, treatment with 10–100nM [Ala1,3,11,15]-Endothelin for 18 hours. [Ala1,3,11,15]-Endothelin enhanced wound repair by promoting cell proliferation rather than migration[6].
In vivo, intravenous administration of [Ala1,3,11,15]-Endothelin (0.1–10nmol/kg) induced a biphasic hemodynamic response in anesthetized rats. During the initial phase (1–3 minutes), [Ala1,3,11,15]-Endothelin caused a significant decrease in mean arterial pressure accompanied by vasodilation in the carotid, coeliac, and iliac arterial regions, along with marked vasoconstriction in the mesenteric and renal arteries. In the later phase (15–20 minutes), [Ala1,3,11,15]-Endothelin increased in blood pressure and systemic vasoconstriction[7].
References:
[1] Nakamichi K, Ihara M, Kobayashi M, et al. Different distribution of endothelin receptor subtypes in pulmonary tissues revealed by the novel selective ligands BQ-123 and [Ala1,3,11,15]ET-1. Biochem Biophys Res Commun. 1992 Jan 15;182(1):144-50.
[2] Webber KM, Pennefather JN, Head GA, et al. Endothelin induces dopamine release from rat striatum via endothelin-B receptors. Neuroscience. 1998 Oct;86(4):1173-80.
[3] Saeki T, Ihara M, Fukuroda T, et al. [Ala1,3,11,15]endothelin-1 analogs with ETB agonistic activity. Biochem Biophys Res Commun. 1991 Aug 30;179(1):286-92.
[4] Wong J, Reddy VM, Hendricks-Munoz K, et al. Endothelin-1 vasoactive responses in lambs with pulmonary hypertension and increased pulmonary blood flow. Am J Physiol. 1995 Dec;269(6 Pt 2):H1965-72.
[5] Schramek H, Wang Y, Konieczkowski M, et al. Endothelin-1 stimulates cytosolic phospholipase A2 in Chinese hamster ovary cells stably expressing the human ETA or ETB receptor subtype. Biochem Biophys Res Commun. 1994 Mar 15;199(2):992-7.
[6] Wren AD, Hiley CR, Fan TP. Endothelin-3 mediated proliferation in wounded human umbilical vein endothelial cells. Biochem Biophys Res Commun. 1993 Oct 15;196(1):369-75.
[7] Bigaud M, Pelton JT. Discrimination between ETA- and ETB-receptor-mediated effects of endothelin-1 and [Ala1,3,11,15]endothelin-1 by BQ-123 in the anaesthetized rat. Br J Pharmacol. 1992 Dec;107(4):912-8.
[Ala1,3,11,15]-Endothelin是一种经过修饰的Endothelin-1线性类似物，特点在于将原始序列中第1，3，11，15位的氨基酸替换为Alanine[1-2]。[Ala1,3,11,15]-Endothelin是内皮素B受体（ETB）的激动剂，对ETB受体的IC50值范围在0.33nM至0.61nM之间，可用于血管收缩及相关受体功能的研究[3-4]。
在体外，[Ala1,3,11,15]-Endothelin（100nM）处理稳定表达人ETB受体的中国仓鼠卵巢细胞（CHO细胞）20分钟，[Ala1,3,11,15]-Endothelin显著刺激胞质磷脂酶A2活性，并促进前列腺素E2的分泌[5]。[Ala1,3,11,15]-Endothelin（10–100nM）处理损伤的人脐静脉内皮细胞（HUVEC）18小时，[Ala1,3,11,15]-Endothelin显著增强细胞单层修复能力，通过促进增殖而非迁移加速伤口愈合[6]。
在体内，[Ala1,3,11,15]-Endothelin（0.1–10nmol/kg）静脉注射诱导了大鼠双相血流动力学反应。[Ala1,3,11,15]-Endothelin在初期（1–3分钟内）引起大鼠平均动脉压显著下降，伴随颈动脉、腹腔和髂动脉区域的血管舒张，同时肠系膜和肾动脉出现明显血管收缩。[Ala1,3,11,15]-Endothelin在后期（15–20分钟）引起大鼠出现血压升高及系统性血管收缩[7]。