Physiol. Res. 48: 9-19, 1999

Detrimental Subtype-Specific Endothelin-1 (ET-1) Signaling in Myocardial Cells: the ETA Mediated Proliferation and ETB Receptor Down-Regulation


Institute of Experimental Pharmacology, Slovak Academy of Sciences, Bratislava, Slovak Republic

Received April 27, 1998
Accepted October 15, 1998

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

© 1999 by the Institute of Physiology, Czech Academy of Sciences