Endothelins (ET-1, 2, and 3) are considered to be very powerful vasoconstrictive substances. In humans, endothelins mediate their actions via two specific G-protein coupled receptors, ET_AR and ET_BR. Both ET_AR and ET_BR are present in the heart and in human myocardium at similar levels.^1,2

The endothelin receptors differ in their ligand specificity. While ET_AR has varying affinities for the endothelin isoforms (ET-1 > ET-2 > ET-3), ET_BR shows no selective affinity.^2,3 

Subsequent studies have demonstrated the presence of endothelins in vascular, as well as in non-vascular, cells and tissues, having multiple biological activities.

Currently, there is increasing evidence that ET-1 may modulate mitogenesis, apoptosis, angiogenesis tumor invasion and the development of metastases.³

Until recently, it was thought that all cellular activities of the endothelins were mediated through their interactions with their cell surface receptors. However, a recent study demonstrated that cardiac nuclei also possess both ET_AR and ET_BR subtypes, which are functional and coupled to signaling mechanisms within the nuclear membrane.²

Hypermethylation of the ET_BR correlated with transcriptional down-regulation and reduced expression of ET_B receptor was observed in several prostate, bladder and colon cancer cell lines.³