AJP - Heart and Circulatory Physiology, Vol 266, Issue 3 959-H966, Copyright © 1994 by American Physiological Society

ARTICLES

Characterization of endothelin receptors mediating contraction of rabbit saphenous vein

G. A. Gray, B. M. Loffler and M. Clozel
Pharma Division, Preclinical Research, Hoffmann-La Roche, Basel, Switzerland.

The goal of this study was to characterize endothelin (ET) receptors mediating contraction of the rabbit saphenous vein. For this purpose, binding and functional studies were performed. Two receptor subtypes mediated contraction in response to ET-1. The first, responsible for 80-90% of maximal contraction, was stimulated with equal potency by ET-1, ET-3, and sarafotoxin S6c. The second, responsible for the remaining contraction, was stimulated more potently by ET-1 than by ET-3 and not by sarafotoxin S6c. The specific ETA receptor antagonist BQ-123 and the inhibitor of protein kinase C (PKC) Ro 31-8220 inhibited ET-1 contraction via the second but not the first receptor. In plasma membranes 125I-labeled ET-1 bound predominantly to a site with characteristics of ETA receptor, whereas 125I-ET-3 bound to two sites with characteristics of ETB receptor, one of high and one of low affinity. Comparison of binding affinity constants and 50% effective concentrations shows that the high-affinity ETB receptor corresponds to the receptor mediating the major part of contraction independently of PKC activation and ETA to the receptor mediating the minor part of contraction via a PKC-dependent mechanism.

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