[Molecular pharmacology of endothelin in the cardiovascular system]

Endothelin-1 (ET-1), ET-2 and ET-3 are 21-amino acid peptides that act to stimulate contraction of many smooth muscle tissues including blood vessels, uterus, bladder, and intestine. In the case of each ET, the 21-amino acid bioactive form is produced from each precursor (referred to as big ET) via specific conversion between Trp-Val (ET-1, ET-2) or Trp-Ile (ET-3). Northern blot analysis of the mRNA for the ET isoform as well as determination of the peptide itself revealed that they are independently expressed in various tissues, indicating that each isoform may play separate physiological or pathophysiological roles. However, the vascular endothelial cells appear to produce only ET-1. Since ET-1 was first discovered, the majority of investigations so far reported have been concerned with this particular peptide. This review will focus on ET-1 with respect to the regulation of its biosynthesis in endothelial cells and its precise pharmacological actions on the cardiovascular system including the cerebral, coronary and renal circulations. Sub-classification of ET receptors was made from molecular biological, biochemical as well as pharmacological points of view. The signal transduction for mechanisms of action was also explained in detail.