Does Targeting the Lipophilic Milieu Provide Advantages for an Endothelin Antagonist?

Fundamental mechanisms of ET-1 synthesis and receptor-specific actions in the vascular wall. Endothelin-1 (ET-1) synthesis begins with the initial gene product Prepro-ET-1 and is processed by series of proteolytic cleavages to form the immediate precursor, Big ET-1. Big ET-1 is cleaved by ECE to become ET-1. Big ET-1 is stored and released along with the more potent peptide, ET-1. ET-1, in turn, acts in an autocrine fashion to activate ET_B receptors in endothelial cells to release vasorelaxing factors such as nitric oxide and prostaglandins. These factors have well-characterized actions to produce vasorelaxation and inhibit growth and proliferation of vascular smooth muscle. On vascular smooth muscle, the primary target is ET_A receptors, which produce vasoconstriction along with mitogenic effects. In some vascular beds and in some pathological conditions, ET_B receptors on vascular smooth muscle mimic the actions of the ET_A receptor. However, little is known about the conditions in which these receptors are physiologically or pathophysiologically significant. ECE, endothelin–converting enzyme.