Activation of circulating platelets accompanies hipercholesterolemia and atherosclerosis and may be caused by impairment of endothelial antiplatelet activity. The aim of this work was to characterise the activity of the main endothelial antiplatelet and antiinflammatory mechanisms (NO, PGI2 and adenosine) in the coronary circulation in hypercholesterolemic mice along the development of atherosclerosis. NO-dependent, PGI2-dependent and adenosine-dependent vasodilations were investigated in the isolated hearts of apoE/LDLR-/- mice before atherosclerosis development and in the presence of atherosclerotic lesions. Levels of metabolites of PGI2 and adenosine in the coronary effluent and the concentration of sCD40L and SAA in plasma were determined. HbNO level in erythrocytes, circulating platelet membrane expression of P-selectin, CD40L and aGPIIb-IIIa and mice exercise capacity were also determined. In apoE/LDLR-/- mice, before development of atherosclerosis, systemic bioavaibility of NO is impaired and circulating platelet CD40L-dependent activity is increased. In the coronary circulation, NO-dependent endothelial function is not impaired and sensitivity to NO and PGI2 production is augmented. In young apoE/LDLR-/- mice, intracoronary adenosine production is impaired and the sensitivity of coronary arteries to adenosine is increased; these phenomena disappear with age. Exercise capacity is preserved, and systemic PGI2 production is increased during exercise. These results suggest that in ApoE/LDL-/- mice adaptive alterations of endothelial NO-, PGI2- and adenosine-dependent function are present and may provide the explanation for the preservation of exercise capacity.