A. Talbodec et al., Aspirin and sodium salicylate inhibit endothelin ETA receptors by an allosteric type of mechanism, MOLEC PHARM, 57(4), 2000, pp. 797-804
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.