Jpn. J. Pharmacol. 72, 261-290 (1996)
Molecular Pharmacology and Pathophysiological Significance of Endothelin
Katsutoshi Goto, Hiroshi Hama and Yoshitoshi Kasuya
Department of Pharmacology, Institute of Basic Medical Sciences, The
University of Tsukuba, Tsukuba, Ibaraki 305, Japan
Abstract: Since the discovery of the most potent vasoconstrictor
peptide, endothelin, in 1988, explosive investigations have rapidly clarified
much of the basic pharmacological, biochemical and molecular biological
features of endothelin, including the presence and structure of isopeptides
and their genes (endothelin-1, -2 and -3), regulation of gene expression,
intracellular processing, specific endothelin converting enzyme (ECE), receptor
subtypes (ETA and ETB), intracellular signal transduction following receptor
activation, etc. ECE was recently cloned, and its structure was shown to
be a single transmembrane protein with a short intracellular N-terminal
and a long extracellular C-terminal that contains the catalytic domain and
numerous N-glycosylation sites. In addition to acute contractile or secretory
actions, endothelin has been 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 antagonists
have been developed. They, as well as current peptide antagonists, markedly
accelerated the pace of investigations into the true pathophysiological
roles of endogenous endothelin-1 in mature animals; e.g., hypertension,
pulmonary hypertension, acute renal failure, cerebral vasospasm, vascular
thickening, cardiac hypertrophy, chronic heart failure, etc. Thus, the interference
with the endothelin pathway by either ECE-inhibition or receptor blockade
may provide an exciting prospect for the development of novel therapeutic
drugs.
Keywords: Endothelin, Endothelin receptor, Signal transduction, Antagonist,
Pathophysiology
Copyright© The Japanese Pharmacological Society 1996
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