Aspirin and sodium salicylate inhibit endothelin ETA receptors by an allosteric type of mechanism

• Published in: Molecular pharmacology Vol. 57; no. 4; p. 797
• Main Authors: Talbodec, A, Berkane, N, Blandin, V, Breittmayer, J P, Ferrari, E, Frelin, C, Vigne, P
• Format: Journal Article
• Language: English
• Published: United States 01-04-2000
• Subjects: Allosteric Regulation - drug effects; Animals; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Aorta; Aspirin - pharmacology; Biological Transport - drug effects; Bosentan; Calcium - metabolism; Cells, Cultured; Drug Synergism; Endothelin Receptor Antagonists; Endothelin-1 - metabolism; Humans; Mammary Arteries - drug effects; Muscle Contraction - drug effects; Rats; Receptors, Endothelin - metabolism; Sodium Salicylate - pharmacology; Sulfonamides - pharmacology
• ISSN: 0026-895X
• DOI: 10.1124/mol.57.4.797

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 Ca(2+) 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 (125)I-ET-1 binding to recombinant rat ETA receptors. Salicylic acid promotes dissociation of (125)I-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 (125)I-ET-1 to ETA receptors. Salicylates do not promote dissociation of (125)I-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.