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Increased platelet aggregation plays a pivotal role in the etiology of cardiovascular disease. Upon platelet aggregation, an increase in free cytoplasmic Ca2+ results in the inhibition of soluble guanylyl cyclase (sGC) and adenylyl cyclase (AC), leading to a decrease in cyclic guaninosine-5#-monophosphate (cGMP) and cAMP, respectively. This leads to the activation of the glycoprotein IIb/IIIa (GPIIb/IIIa) fibrinogen receptor, resulting in platelet shape change. Aged garlic extract (AGE) decreases platelet aggregation; however, the mechanisms involved are not clearly defined.Our objective was to investigate the effects of AGE on intraplatelet cell signaling and platelet shape change.Platelets from 14 participants were studied. Platelet aggregation was induced by ADP in the presence of AGE up to a concentration of 6.25% (vol:vol) alone or in combination with 3-morpholinosydnonimine (Sin-1), a nitric oxide donor. The experiments with AGE were repeated in the presence of 3-isobutyl-1-methylxanthine (IBMX), a phosphodiesterase inhibitor. In a series of separate experiments, platelet aggregation was induced in the presence of either 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), an sGC inhibitor, or 9-(tetrahydro-2-furanyl)-9H-purin-6-amine (SQ22536), an AC inhibitor, or a combination of both in the presence of IBMX and AGE. Intraplatelet cGMP and cAMP were measured. The platelets were also subjected to scanning electron microscopic analysis, and their binding to fibrinogen was determined.AGE decreased platelet aggregation at all concentrations tested; this decrease was more marked in the presence of Sin-1 and ranged between 15% and 67%.The presence of IBMX also led to a decrease (17-35%) in platelet aggregation at all AGE concentrations and a significant decrease in the amounts of cGMP (24-41%) and cAMP (19-70%), respectively, in the presence of ODQ and SQ22536. The presence of AGE significantly inhibited the binding of activated platelets to fibrinogen, preventing changes in platelet shape.These results indicate that AGE inhibits platelet aggregation by increasing cyclic nucleotides and inhibiting fibrinogen binding and platelet shape change. J Nutr 2016;146(Suppl):410S-5S.