**5.4 Endothelin receptors**

In the vasculature, contraction or vasodilation by ET-1 are mediated by two different receptor subtypes, ETA and ETB [39], belonging to the family of heptahelical G-protein-coupled receptors located on vascular smooth muscle cells (VSMCs) and endothelial cells. The endothelin receptor subtypes are distinctively localized. The ETA-receptor subtype mainly mediates the vasoconstrictor activity. The receptor subtype is widely co-localized with ETR-B in vascular smooth muscle of cardiovascular tissues [40, 41], cardiopulmonary [42], central nervous system [43], retina [44], and placenta. However, ETR-A is not expressed on endothelial cells and renal-collecting duct cells. ETRB is highly expressed in the endothelium, and under pathophysiological conditions, the expression of ETB receptor subtype also increases on VSMCs and produces vasoconstriction. ETR-A has high affinity for both ET-1 and ET-2, whereas ETR-B has a similar affinity for all ET isoforms [45]. ETRB has broader effects compared to ETR-A and has roles to play in ET-1 clearance, endothelial cell survival, signaling to NO synthase (eNOS) and NO production, prostacyclin synthesis, and inhibition of ECE-1 [46]. Interaction of ET-1 with its receptors increases intracellular calcium, leading to phosphorylation and activation of myosin light chain to produce vasoconstriction [47]. Vasodilatory effect by ET-1 is mediated through ETB receptors on endothelial cells which increase the production of NO and PGI2.

**Endothelin receptor antagonists (ERAs)** have been developed to block the effects of ET-1 in a variety of cardiovascular conditions. Three main kinds of ERAs exist:


*An Overview of Gene Variants of Endothelin-1: A Critical Regulator of Endothelial Dysfunction DOI: http://dx.doi.org/10.5772/intechopen.108108*

Sitaxentan (withdrawn in 2010 after acute liver failure leading to death), ambrisentan, and bosentan are mainly used for the treatment of pulmonary arterial hypertension (PAH), while atrasentan is an experimental anticancer drug.
