EFFECT OF 17-BETA-ESTRADIOL ON INHIBITION OF PLATELET-AGGREGATION IN-VITRO IS MEDIATED BY AN INCREASE IN NO SYNTHESIS

The low prevalence of coronary heart disease in premenopausal women an d its increase after menopause are well established. Although estrogen is thought to play a role in protecting the vasculature, the mechanis m has not been fully clarified. The contribution of platelets to ather osclerotic cardiovascular diseases is well recognized. The present stu dy focused on the still-controversial effect of estrogen on platelet f unction. We investigated the in vitro effects of estrogen on human pla telets, including their aggregation, Ca2+ metabolism, the synthesis of cyclic nucleotides, and NO (nitrite/nitrate) synthesis after stimulat ion with thrombin or ADP. Pretreatment of platelets with 17 beta-estra diol reduced the platelet aggregation induced by thrombin or ADP, wher eas 17 alpha-estradiol had no effect. 17 beta-Estradiol accelerated th e recovery of [Ca2+](i) after the agonist-induced peak and reduced the area under the curve of accumulated platelet [Ca2+](i) but did not al ter the baseline [Ca2+](i), Ca2+ influx induced by thrombin or ADP, th e release of Ca2+ from internal stores, or the size of internal Ca2+ s tores. Pretreatment of platelets with 17 beta-estradiol had no effect on the intracellular concentration of cAMP but increased that of cGMP in agonist-stimulated platelets. Additionally, 17 beta-estradiol incre ased the platelet concentration of nitrite/nitrate in a dose-dependent manner. These effects of 17 beta-estradiol on platelet aggregation, C a2+ metabolism, and NO synthesis were abolished by exposure to N-G-mon omethyl-L-arginine, an NO synthesis inhibitor. These results suggest t hat 17 beta-estradiol plays an important role in inhibiting platelet a ggregation by promoting Ca2+ extrusion or reuptake activity that is de pendent on the production of cGMP by increasing NO synthesis.