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 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.
Talbodec
A
A
Institut de Pharmacologie Moléculaire et Cellulaire du Centre National de la Recherche Scientifique, Valbonne, France.
Berkane
N
N
Blandin
V
V
Breittmayer
J P
JP
Ferrari
E
E
Frelin
C
C
Vigne
P
P
D000494:Allosteric Regulation / Q000187:drug effects; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001011:Aorta; D001241:Aspirin / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D000077300:Bosentan; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D004357:Drug Synergism; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000378:metabolism; D006801:Humans; D008323:Mammary Arteries / Q000187:drug effects; D009119:Muscle Contraction / Q000187:drug effects; D051381:Rats; D017466:Receptors, Endothelin / Q000378:metabolism; D012980:Sodium Salicylate / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D017466:Receptors, Endothelin; D013449:Sulfonamides; D000077300:Bosentan; D001241:Aspirin; D002118:Calcium; D012980:Sodium Salicylate