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

Abstract

The endothelin (ET) system comprises three 21-amino acid peptides (ET-1, ET-2, and ET-3). Of these, only ET-1 appears to play an important physiological and pathophysiological role in the cardiovascular system. ET-1 acts mainly in a paracrine fashion and is an extremely potent and long-lasting vasoconstrictor. ET-1 is released principally from endothelial cells and is initially synthesized as Prepro-ET-1, a 203-amino acid peptide, which is cleaved into big ET-1, a 38-amino acid peptide. Big ET-1 is in turn cleaved into its functional form (ET-1) by endothelin converting enzyme-1 (1–3). As shown in Figure 1, the hemodynamic and proliferative effects of ET-1 are mediated through two receptor subtypes: ETA receptors, located on vascular smooth muscle cells (VSMCs), are responsible for the vasoconstricting effects of ET-1; and ETB receptors, located on vascular endothelial cells, are responsible for the vasodilating effects of ET-1. Vasodilation is mediated by endothelial-derived relaxing factors including nitric oxide (NO) (4–6). A subpopulation of ETB receptors is also found on VSMCs and induces vasoconstriction when activated (7). In addition to its vasoconstrictor and pressor effects, ET-1 can induce hypertrophy and hyperplasia of cardiomyocytes (8), stimulate fibroblast proliferation (9), increase extracellular matrix production (10), and stimulate a pro-inflammatory phenotype (11). ET-1 also alters the generation of vasomediators other than NO, including prostacyclin and platelet-activating factors (7). Circulating plasma ET-1 concentrations are elevated in atherosclerosis, arterial hypertension, heart failure, and pulmonary arterial hypertension (PAH) as compared to those concentrations observed in the normal state (12). ET-1 plasma concentrations also correlate inversely with reduced pulmonary function (13) and survival in patients with PAH (14).