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Use of the endothelin antagonists BQ‐123 and PD 142893 to reveal three endothelin receptors mediating smooth muscle contraction and the release of EDRF
Author(s) -
Warner Timothy D.,
Allcock Graham H.,
Corder Roger,
Vane John R.
Publication year - 1993
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1993.tb13879.x
Subject(s) - receptor , endothelin receptor , endocrinology , medicine , receptor antagonist , endothelins , contraction (grammar) , thoracic aorta , antagonist , aorta , endothelin 1 , biology , chemistry
1 We have compared the receptors mediating the contractions of rings of rat thoracic aorta or rabbit pulmonary artery and rat stomach strips in response to the endothelin/sarafotoxin (ET/SX) family of peptides and to those mediating endothelium‐dependent vasodilatations within the isolated perfused mesentery of the rat. To discriminate ET A receptors from ET B receptors we have used the criteria that ET‐1 is more active than SX6c on ET A receptors, and that the ET/SX peptides are equiactive on ET B receptors. We have also assessed the effects of the ET A receptor‐selective antagonist BQ‐123, and the non‐selective ET receptor antagonist PD 142893 on the responses of each preparation to the ET/SX peptides. 2 ET‐1‐induced constrictions of the rat thoracic aorta (EC 50 3 × 10 −10 m ), a prototypic ET A receptor‐mediated response, or isolated perfused mesentery of the rat were antagonized by BQ‐123 (10 −5 m ) or PD 142893 (10 −5 m ). SX6c did not constrict either the rat isolated perfused mesentery or the rat thoracic aorta. Thus, ET A receptors mediate these constrictions. 3 ET‐1 and SX6c were approximately equipotent in constricting rabbit pulmonary artery rings (EC 50 s 3–6 × 10 −10 m ). Neither BQ‐123 (10 −5 m ) nor PD 142893 antagonized the contractions induced by ET‐1. These effects suggest mediation by ET B receptors but PD 142893 (10 −5 m ) did give a 3 fold antagonism of constrictions induced by SX6c. 4 SX6c was more potent than ET‐1 in contracting the rat stomach strip (threshold concentrations 10 −10 and 3 × 10 −10 m ). Contractions to ET‐1 or SX6c were unaffected by BQ‐123 (10 −5 m ), again indicative of ET B receptor‐mediated events. PD 142893 (10 −5 m ) was ineffective against ET‐1 but produced a 3 fold antagonism of SX6c. 5 In the rat isolated perfused mesentery ET‐1 or SX6c (0.3–300 pmol) were equipotent in producing dose‐related vasodilatations that were unaffected by BQ‐123 (10 −6 m ), indicative of an ET B receptor‐mediated response. In contrast to the other ET B ‐mediated responses, PD 142893 (10 −6 m ) strongly antagonized these vasodilatations. 6 Thus, ET A receptors mediate constrictions of the rat thoracic aorta and rat isolated perfused mesentery whereas ET B receptors mediate constrictions of the rabbit pulmonary artery and rat stomach strip and endothelium‐dependent dilatations within the mesentery. However, within the group of ET B receptor‐mediated responses, endothelium‐dependent vasodilatations are sensitive to PD 142893, whereas contractions of the isolated smooth muscle preparations are not. Thus, the receptor present on the endothelium responsible for the release of nitric oxide in response to the ET/SX peptides is most probably different from that present on smooth muscle that mediates BQ‐123‐insensitive contractions.