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

Aspirin is a commonly used drug with a wide pharmacological spectrum includ ing antiplatelet, anti-inflammatory, and neuroprotective actions. This stud y shows that aspirin and sodium salicylate, its major blood metabolite, rev erse contractile actions of endothelin-1 (ET-1) in isolated rat aorta and h uman 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 comp etitive. Salicylates inhibit I-125-ET-1 binding to recombinant rat ETA rece ptors. Salicylic acid promotes dissociation of I-125-ET-1 ETA receptor comp lexes both in the absence and the presence of unlabeled ET-1. It has no inf luence on the rate of association of I-125-ET-1 to ETA receptors. Salicylat es do not promote dissociation of I-125-ET-1 ETB receptor complexes. Salicy lates potentiate relaxing actions of receptor antagonists such as bosentan. It is concluded that salicylates are allosteric inhibitors of ETA receptor s. The results also suggest that: 1) irreversible ET-1 binding probably lim its actions of receptor antagonists in vivo, and 2) an association of salic ylates and ETA receptor antagonists should be used to evaluate the physiopa thological role of ET-1 and may be of therapeutic interest in the treatment of ischemic heart disease.