MOLECULAR PHARMACOLOGY AND PATHOPHYSIOLOGICAL SIGNIFICANCE OF ENDOTHELIN

Since the discovery of the most potent vasoconstrictor peptide, endoth elin, in 1988, explosive investigations have rapidly clarified much of the basic pharmacological, biochemical and molecular biological featu res of endothelin, including the presence and structure of isopeptides and their genes (endothelin-1, -2 and -3), regulation of gene express ion, intracellular processing, specific endothelin converting enzyme ( ECE), receptor subtypes (ET(A) and ET(B)), intracellular signal transd uction following receptor activation, etc. ECE was recently cloned, an d its structure was shown to be a single transmembrane protein with a short intracellular N-terminal and a long extracellular C-terminal tha t contains the catalytic domain and numerous N-glycosylation sites. In addition to acute contractile or secretory actions, endothelin has be en shown to exert long-term proliferative actions on many cell types. In this case, intracellular signal transduction appears to converge to activation of mitogen-activated protein kinase. As a recent dramatic advance, a number of non-peptide and orally active receptor antagonist s have been developed. They, as well as current peptide antagonists, m arkedly accelerated the pace of investigations into the true pathophys iological roles of endogenous endothelin-1 in mature animals; e.g., hy pertension, pulmonary hypertension, acute renal failure, cerebral vaso spasm, vascular thickening, cardiac hypertrophy, chronic heart failure , etc. Thus, the interference with the endothelin pathway by either EC E-inhibition or receptor blockade may provide an exciting prospect for the development of novel therapeutic drugs.