Detrimental Subtype-Specific
Endothelin-1 (ET-1) Signaling in Myocardial Cells: the ETA
Mediated Proliferation and ETB Receptor Down-Regulation
J. DŘÍMAL, M. MISLOVIČOVÁ, A.
ISMAIL, F. MONČEK
Institute of Experimental Pharmacology, Slovak
Academy of Sciences, Bratislava, Slovak Republic
Received April 27, 1998
Accepted October 15, 1998
Summary
Many physiological and pathological processes in the cardiac
tissue have been shown to be associated with a release of
endothelin (ET) peptides and with induction of specific
ET-receptors and G-protein-coupled ion channels. However, the
exact mechanism regulating ET-receptors in the myocardium is
controversial. The response to ET-1, the most important member
of the ET family, is rapidly attenuated by down-regulation of
ET-receptors. The internalization of ET-1 bound to two
subclasses of specific receptors (ETA and ETB) that are abundant
in the myocardium has been hypothesized to activate and/or
inhibit a variety of intracellular signal transducing systems.
The [125I]ET-1, BQ-3020 and selective ET-antagonists were used
to study the subtype-selective component of regulation of ET-1
receptors in myocardial membranes. We determined the
characteristics of [125I]ET-1 binding and [3H]thymidine
incorporation in whole cell saturation studies and measured Ca
2+ channel induction and the total number of inactive Ca2+
channels in photoaffinity studies with [3H]azidopine. Here we
demonstrate four important components of the complex ET-1
response in human, porcine and rat myocardium, leading to
aberrant responses of cells. After ET-1 induction, adaptive
subtype-ETB selective down-regulation predominated in human
embryonic fibroblasts, in porcine membrane vesicles and in
microsomal membranes of renal hypertensive rats, with
preferential high affinity ET-1 binding to ETA receptors and
with the resultant ETA mediated proliferative and mitogenic
activation of human fibroblasts. The ET-1 induction was also
accompanied by profound inactivation of Ca2+ channels in
myocardial membranes.
Key words
Ligand binding - Endothelin-1 - ETA-ETB receptors -
Photoaffinity labeling - Ca2+ channels - Human fibroblasts -
Porcine myocardium - Microsomal membranes - Rat renal
hypertension
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