Antiplatelet effects of ticlopidine are reduced in experimental hypercholesterolemia

This study determines the antiplatelet effects of oral ticlopidine (100 mg/kg x day) in experimental hypercholesterolemia. Rabbits were fed either a standard diet or a cholesterol-enriched diet (0.5% for 3 months, 1% for 1 month). In normocholesterolemic controls ADP-, but not collagen-induced platelet aggregation was inhibited by ticlopidine treatment. This was accompanied by a significantly enhanced inhibition of ADP-induced platelet aggregation and stimulation of cyclic AMP accumulation by iloprost. Hypercholesterolemia considerably attenuated the inhibition of ADP-induced aggregation by ticlopidine but did not change its effect on the iloprost-induced inhibition of platelet function and cyclic AMP formation. ADP-induced platelet-derived thromboxane formation was considerably greater in hypercholesterolemic rabbits and not reduced by ticlopidine. Ticlopidine did also not significantly influence the extent and severity of atherosclerotic plaque formation although a tendency for improvement was observed in a subgroup of animals. The data suggest that hypercholesterolemia attenuates the inhibitory effect of ticlopidine on ADP-induced platelet aggregation. This might be related to the stimulation of thromboxane formation by ADP in hypercholesterolemia. The maintained protection from ADP-induced inhibition of cAMP accumulation suggests a minor role of this mechanism in the progression of hypercholesterolemia-induced vessel disease in this model.