RT Journal Article
SR Electronic
T1 Aspirin and Sodium Salicylate Inhibit Endothelin ETA Receptors by an Allosteric Type of Mechanism
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 797
OP 804
DO 10.1124/mol.57.4.797
VO 57
IS 4
A1 Anne Talbodec
A1 Nathalie Berkane
A1 Virginie Blandin
A1 Jean Philippe Breittmayer
A1 Emile Ferrari
A1 Christian Frelin
A1 Paul Vigne
YR 2000
UL http://molpharm.aspetjournals.org/content/57/4/797.abstract
AB Aspirin is a commonly used drug with a wide pharmacological spectrum including antiplatelet, anti-inflammatory, and neuroprotective actions. This study shows that aspirin and sodium salicylate, its major blood metabolite, reverse contractile actions of endothelin-1 (ET-1) in isolated rat aorta and human mammary arteries. They also prevent the intracellular Ca2+ mobilizing action of ET-1 in cultured endothelial cells but not those of neuromedin B or UTP. Inhibition of the actions of ET-1 by salicylates is apparently competitive. Salicylates inhibit 125I-ET-1 binding to recombinant rat ETA receptors. Salicylic acid promotes dissociation of125I-ET-1 ETA receptor complexes both in the absence and the presence of unlabeled ET-1. It has no influence on the rate of association of 125I-ET-1 to ETA receptors. Salicylates do not promote dissociation of 125I-ET-1 ETB receptor complexes. Salicylates potentiate relaxing actions of receptor antagonists such as bosentan. It is concluded that salicylates are allosteric inhibitors of ETA receptors. The results also suggest that: 1) irreversible ET-1 binding probably limits actions of receptor antagonists in vivo, and 2) an association of salicylates and ETA receptor antagonists should be used to evaluate the physiopathological role of ET-1 and may be of therapeutic interest in the treatment of ischemic heart disease.