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Steroids ; 77(3): 260-8, 2012 Feb.
Article in English | MEDLINE | ID: mdl-22182832

ABSTRACT

Dehydroepiandrosterone (DHEA) and its sulfated form, DHEA-S, are the most abundant steroids circulating in human blood. DHEA stimulates endothelial cells to release high amounts of nitric oxide in the circulation. Nitric oxide activates guanylyl cyclase in platelets thus decreasing the responsiveness of these cells to physiological agonists. However, the impact of DHEA-S and DHEA on platelet function and their possible role in modulating the response of human platelets to physiological agonists were not yet investigated. Here, DHEA-S, but not DHEA, inhibited in vitro thrombin-dependent platelet aggregation in a dose-dependent manner. DHEA-S exerted this effect by decreasing thrombin-dependent dense granule secretion, and so impairing the positive feed-back loop provided by ADP. Furthermore, DHEA-S inhibited thrombin-dependent activation of Akt, ERK1/2, and p38 MAP kinase. Although both DHEA-S and DHEA directly activated in platelets the inhibitory cGMP/PGK/VASP pathway, these events were not responsible for the inhibitory action of DHEA-S in platelets. In addition DHEA-S acted in synergism with nitric oxide in inhibiting platelet aggregation. In conclusion DHEA-S inhibited platelet activation caused by a mild stimulus without completely hampering platelet functionality and thus DHEA-S may participate in the physiological mechanisms that maintain circulating platelets in a resting state. The role played by DHEA-S could be relevant mainly when the functionality of the vascular endothelium is compromised.


Subject(s)
Blood Platelets/drug effects , Dehydroepiandrosterone Sulfate/pharmacology , Dehydroepiandrosterone/pharmacology , Platelet Aggregation Inhibitors/pharmacology , Platelet Aggregation , Adenosine Triphosphate/metabolism , Blood Platelets/metabolism , Dose-Response Relationship, Drug , Humans , Immunoblotting , MAP Kinase Signaling System , Nitric Oxide/metabolism , Phosphorylation , Thrombin/pharmacology
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