Introduction

Endothelin-1 is a 21-amino acid peptide that was identified in 1988 as a potent constrictor substance produced by vascular endothelial cells [1]. Endothelin-1 belongs to a family of peptides which also includes endothelin-2 and endothelin-3. These isopeptides are encoded by separate genes. It was originally thought that endothelin-1 was produced exclusively by endothelial cells, but it was demonstrated subsequently that it can be produced by several different cell types, such as vascular smooth muscle cells and cardiac myocytes. The expression of endothelin-1 mRNA is stimulated by different growth factors, cytokines, vasoactive substances such as angiotensin II and catecholamines, shear stress, hypoxia and oxidized low-density lipoproteins (Figure 35.1). The expression is inhibited by nitric oxide and atrial natriuretic factor.

Endothelin-1 is synthesized from a larger prepropeptide which is further processed to the 38-amino acid intermediate big endothelin-1 (Figure 35.1). Big endothelin-1 is cleaved to the 21-amino acid endothelin-1 by a family of endothelin-converting enzymes [1]. The endothelin-converting enzyme is located both intracellularly and in connection with the cell membrane of endothelial cells and vascular smooth muscle cells (Figure 35.1). The conversion of big endothelin-1 to endothelin-1 is essential for its biological activity.

The receptors for endothelin-1 are widely distributed in the cardiovascular system. Two different subtypes of ET receptors, ETA and ETB, have been cloned and characterized [1]. In the vascular wall, the ETA receptor is present on the vascular smooth muscle cells and activation of this receptor leads to vasoconstriction (Figure 35.1).