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.
Hohlfeld
T
T
Institut für Pharmakologie, Heinrich-Heine-Universität Düsseldorf, Germany.
Scharnowski
F
F
Braun
M
M
Schrör
K
K
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000818:Animals; D001018:Aortic Diseases / Q000517:prevention & control; D001161:Arteriosclerosis / Q000517:prevention & control; D001711:Biotransformation; D002791:Cholesterol, Dietary / Q000008:administration & dosage / Q000633:toxicity; D003094:Collagen / Q000494:pharmacology; D000242:Cyclic AMP / Q000096:biosynthesis; D006937:Hypercholesterolemia / Q000097:blood* / Q000139:chemically induced; D016285:Iloprost / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D008099:Liver / Q000378:metabolism; D008297:Male; D010974:Platelet Aggregation / Q000187:drug effects*; D011817:Rabbits; D015398:Signal Transduction; D013929:Thromboxane B2 / Q000096:biosynthesis*; D013988:Ticlopidine / Q000493:pharmacokinetics / Q000494:pharmacology*
D002791:Cholesterol, Dietary; D013929:Thromboxane B2; D000244:Adenosine Diphosphate; D003094:Collagen; D000242:Cyclic AMP; D016285:Iloprost; D013988:Ticlopidine; D007213:Indomethacin