Abstract
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.
Footnotes
- Received July 12, 1999.
- Accepted December 28, 1999.
-
Send reprint requests to: Dr. Christian Frelin, Institut de Pharmacologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique Unité Propre de Recherche 411, 660 route des lucioles, 06560 Valbonne, France. E-mail:frelin{at}ipmc.cnrs.fr
-
This work was supported by the Centre National de la Recherche Scientifique and the Fondation de France.
- The American Society for Pharmacology and Experimental Therapeutics
MolPharm articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|