Vol. 57, Issue 4, 797-804, April 2000

Aspirin and Sodium Salicylate Inhibit Endothelin ETA Receptors by an Allosteric Type of Mechanism

Anne Talbodec, Nathalie Berkane, Virginie Blandin, Jean Philippe Breittmayer, Emile Ferrari, Christian Frelin, and Paul Vigne

Institut de Pharmacologie Moléculaire et Cellulaire du Centre National de la Recherche Scientifique (A.B., N.B., V.B., C.F., P.V.), Valbonne, France; Institut National de la Santé et de la Recherche Médicale U343 (J.P.B.), Hôpital de l'Archet, Nice, France; and Département de Cardiologie (E.F.), Hôpital Pasteur, Nice, France

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 of ¹²⁵I-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.