The characteristics of platelets from seven 5-7-month-old homozygous Watanabe heritable hyperlipidemic (WHHL) rabbits (plasma cholesterol, 13.9±1.7 mM, mean±SEM) were compared with those of platelets from normocholesterolemic age/weight-and sex-matched control rabbits (plasma cholesterol, 2.2±0.3 mM). Whole-blood platelet count and platelet size and protein content were not different in the two groups of rabbits, and the platelets from the WHHL rabbits were not enriched in cholesterol as indicated by identical mean cholesterol: phospholipid molar ratios (C/P). Responses of washed platelets stimulated with various agonists were studied to determine the effects of the genetically determined hypercholesterolemia on the various pathways of platelet aggregation in the absence of plasma components. In platelets from WHHL rabbits compared with controls, aggregation induced by ADP ( H ypercholesterolemia is recognized as a major risk factor for atherosclerosis; however, its effects on platelets, which are involved in the development, progression, and thromboembolic complications of atherosclerosis, have not yet been thoroughly established. In patients with familial hypercholesterolemia (type II hyperbetalipoproteinemia), platelet aggregation, secretion of granule contents, and arachidonic acid metabolism via the cyclooxygenase pathway have been reported to be enhanced in some experiments, 1 -8 but enhancement was not evident in others.69 -10 Platelet hypersensitiv- Received September 4, 1990; revision accepted January 11, 1991. ity has also been reported to be associated with diet-induced hypercholesterolemia in experimental animals, 11 " 20 and we 21 have recently observed that platelets from cholesterol-fed rabbits are hypersensitive to aggregation induced in at least two ways: by thromboxane A 2 (TxA 2 ) and by a thrombin-induced mechanism independent of TxA 2 .The Watanabe heritable hyperlipidemic (WHHL) rabbit is an animal model of familial hypercholesterolemia (for review, see Reference 22) in which atherosclerotic lesions commonly develop in the aorta by at least 3 months of age.23 -24 A recent abstract indicates that platelets from WHHL rabbits are hyperreactive in terms of secretion of carbon-14-labeled serotonin from prelabeled platelets stimulated with a low concentration of collagen.25 However, a detailed examination of the functions of platelets from WHHL rabbits compared with those of platelets from normocholesterolemic control rabbits without atherosclerosis has not been reported previously. With platelets from WHHL rabbits, we were able to study the effects of hypercholesterol-
The effects of ethanol on platelets from rabbits with two different types of hypercholesterolemia, diet-induced and genetically determined, were investigated. There were no differences between the hypercholesterolemic groups and their controls in the extent of (primary) ADP-induced aggregation of washed platelets, and this aggregation was not inhibited by ethanol. Platelets from cholesterol-fed rabbits were more sensitive to aggregation and secretion induced by collagen, whereas platelets from Watanabe heritable hyperlipidemic (WHHL) rabbits were less sensitive. Ethanol inhibited collagen-induced responses of platelets from both hypercholesterolemic groups, but the extent of inhibition of aggregation was not different compared with controls. Because ethanol did not affect U46619-induced responses of aspirin-treated platelets, ethanol does not inhibit aggregation and secretion stimulated by collagen via an effect on thromboxane A 2 (TxA 2 )-induced responses. Platelets from cholesterol-fed rabbits were more sensitive to thrombin even when TxA 2 formation was blocked by aspirin, and inhibition of aggregation by ethanol was less in cholesterol-fed rabbits than in controls. However, neither the extent of thrombininduced responses nor the inhibitory effect of ethanol was different in platelets from WHHL rabbits compared with controls. Thus, different etiologies of hypercholesterolemla produce different changes in platelet function, and ethanol has different effects on the platelets from cholesterol-fed rabbits compared with the platelets from WHHL rabbits. The inhibitory effect of ethanol on the thrombin-induced aggregation of platelets from cholesterol-fed rabbits is attenuated compared with controls, and this finding contrasts with the reported greater inhibitory effect of ethanol on platelets enriched with saturated fats. (Arteriosclerosis and Thrombosis 1992;12:437-445) KEY WORDS • platelet function heritable hyperlipidemic rabbits • hypercholesterolemia • ethanol • aspirin • Watanabe
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