Demonstrates the existence of two distinct endothelin receptor subtypes with different tissue distributions and affinities for ET-1 and ET-3.
Distinguishes ET receptor subtypes in animal tissues; leaves open their roles and targeting in human cardiovascular disease.
Endothelin-1 (ET-1) and ET-3 caused constrictions of endothelium-denuded porcine coronary artery strips with different concentration-response curves: a typical sigmoidal curve to ET-1 and a two-phase sigmoidal curve to ET-3. Binding assays using a membrane preparation demonstrated different Bmax values for [125I]ET-1 and [125I]ET-3 binding. In addition, [125I]ET-1 binding was inhibited by ET-1 and ET-3 with different potencies (ET-1 greater than ET-3), while [125I]ET-3 binding was inhibited by both ETs equally. From these results, two distinct ET receptor subtypes were proposed in the artery; site 1 (selective to ET-1) and site 2 (equally sensitive to both ETs). However, only site 1 was identified on cultured arterial smooth muscle cells (VSMCs) by the binding assay, and this was confirmed since only ET-1 (not ET-3) caused a significant increase in the intracellular free Ca2+ concentration. Therefore, it seems likely that vasoconstriction is mediated via the binding of ET-1 to site 1 (VSMCs) and site 2 (non-VSMCs), or the binding of ET-3 to site 2 (non-VSMCs). Furthermore, site 2 was predominant in nonvascular tissues such as lung, kidney, and cerebellum, thereby suggesting that site 1 may exist in limited tissues such as VSMCs.
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Ihara et al. (1991) studied this question.
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