The purpose of this study is to better understand how hyperlipidemia alters the modulating action of prostaglandin E1 (PGE1) on platelet function. Using our previously characterized rat model of atherogenesis, we demonstrate that the parenteral lipid emulsions, Lipofundin-S and Liposyn, significantly (p < or = 0.05) enhance baseline platelet aggregation. In addition, dose response curves show that in all animals, PGE1 substantially inhibits platelet aggregation at 10(-7) to 10(-6) M, while significantly stimulating platelet function at lower doses. However, at all PGE1 concentrations, aggregation values are higher in platelets from lipid-treated vs. control rats, showing that hyperlipidemia significantly reduces the ability of high concentrations of PGE1 to inhibit platelet activity, based on the absolute values of the controls. Also, dose response curves for PGE1 on platelet aggregation show a marked similarity in shape for control ratsvs. normal humans. Thus, this study demonstrates that hyperlipidemia significantly alters the platelet modulating action of prostaglandin E1, and it shows that PGE1 can either inhibit or stimulate platelet activity in both rat and human platelets.