Are there different ETB receptors mediating constriction and relaxation?
Because certain antagonists of endothelin (ET) ETB receptors (such as the mixed ETA+ETB antagonist PD 142893 or the selective ETB receptor antagonist BQ-788) were shown to antagonize the ETB-mediated dilatation to ET-1 but not the ETB-mediated constriction to ET-1, the existence of two subtypes of to ET-1, the existence of two subtypes of ETB receptors was suggested. The goal of the present study was to further explore this absence of functional antagonism of ETB-mediated constriction by so-called ETB receptor antagonists. In rat tracheal rings denuded of epithelium, Ro 46-8443, a selective ETB receptor antagonist, did not shift the concentration-response curve of ET-1 but antagonized sarafotoxin S6c-induced contractions. However, the ET-1-mediated contractions could be attributed to ETB receptor activation, because BQ-123 had no inhibitory effect except at high doses of ET-1. Preincubation of tracheal rings with BQ-123 (10(-5) M) to block ETA receptors revealed an antagonist effect of Ro 46-8443 on contractions induced by ET-1. By analogy with these pharmacologic experiments, desensitization of ETB receptors by preincubation with sarafotoxin S6c did not modify contractile responses to ET-1 except when the tracheal rings were exposed to BQ-123. We conclude that on rat tracheal rings, ET-1 and sarafotoxin S6c activate a common ETB receptor. However, blockade of ETB receptors is not sufficient for inhibition of ET-1-mediated responses because of cross-talk between receptors that allows ETA to compensate for a blockade of ETB receptors. This study suggests that the endothelial ETB receptor mediating dilatation and the smooth muscle cell ETB receptor mediating constriction may not represent two different subtypes.
Clozel
M
M
Pharma Division, F. Hoffmann-La Roche, Ltd., Basel, Switzerland.
Gray
G A
GA
D000818:Animals; D004305:Dose-Response Relationship, Drug; D016232:Endothelins / Q000494:pharmacology; D008297:Male; D010456:Peptides, Cyclic / Q000494:pharmacology; D051381:Rats; D011921:Rats, Inbred WKY; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000502:physiology*; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects
D016232:Endothelins; D010456:Peptides, Cyclic; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; C072247:cyclo(Trp-Asp-Pro-Val-Leu)