Function of the endothelinB receptor in cardiovascular physiology and pathophysiology

Abstract One of the two receptors by which the potent vasoactive effects of endothelin (ET)-1 are mediated is the ET B receptor (ET BR ), which is found in several tissues, but, more importantly from a cardiovascular point of view, on the endothelial cell. The endothelial cell also has the unique capability of releasing ET-1, as well as other factors, such as the endothelial-derived relaxing factors and prostacyclin, which counteract the myotropic effects of the peptide. The secretory and contractile responses to ET-1 rely on G-protein-coupled ET BR s, as well as ET A -G-protein-coupled receptor-like proteins. The mitogenic properties of ET-1 via ET A receptors (ET AR s) coupled to mitogen-activated protein kinases and tyrosine kinases on the vascular smooth muscle may occur in conjunction with the anti-apoptotic characteristics of the endothelial ET BR s. Interestingly, most of the relevant antagonists and agonists for both ET AR s and ET BR s have been developed by the pharmaceutical industry. This highlights the therapeutical potential of compounds that act on ET receptors. In normal as well as in physiopathological conditions, the ET BR plays an important role in the control of vascular tone, and must be taken into account when using ET receptor antagonists for the treatment of cardiovascular diseases. For the management of congestive heart failure, renal failure and primary pulmonary hypertension, the most recent literature supports the use of selective ET AR antagonists rather than mixed antagonists of ET AR s and ET BR s. Nonetheless, validation of this view will have to await the first clinical trials comparing the actions of ET A to mixed ET A /ET B receptor antagonists.