ET_B

Endothelin receptor ET_B is a G protein-coupled endothelin receptor that regulates vascular function through endothelial relaxation, endothelin-1 clearance, and context-dependent smooth muscle contraction^[1][2]. Mechanistically, endothelial ET_B activation promotes nitric oxide, prostacyclin, and endothelium-derived hyperpolarizing factor release, thereby opposing ET-1-driven vasoconstriction^[1][2]. In human renal and splanchnic circulation, ET_A receptors mediate ET-1-induced vasoconstriction, whereas ET_B receptors clear ET-1 and modulate vascular tone by altering plasma ET-1 concentration^[1]. Endothelial-cell-specific ET_B knockout mice show endothelial dysfunction, decreased endogenous NO release, and increased plasma ET-1, supporting ET_B as a tonic vasodilator receptor^[3]. In pulmonary disease models, ET_B receptor deficiency increases lung endothelin levels, hypoxia-related vascular leak, HIF-1α, and VEGF content^[4]. Compared with ET_A, which preferentially binds ET-1 and drives vasoconstriction, ET_B binds ET-1 and ET-3 and can function as a clearance, endothelial survival, relaxation, or contractile receptor depending on tissue localization^[3][5][4]. For experimental applications, ET_B-selective agonists such as IRL1620 or sarafotoxin S6c and antagonists such as BQ788 help distinguish endothelial ET_B signaling from ET_A-dominant vasoconstriction^[4][6].